CCK-1 receptor modulators

ABSTRACT

There are provided by the present invention certain pyrazole based CCK-1 receptor modulators.

This invention relates to CCK-1 receptor modulators for the treatment ofgastrointestinal and CNS disorders. More particularly, this inventionrelates to certain pyrazole compounds useful as selective agonists orantagonists of the CCK-1 receptor as well as methods for making suchcompounds.

BACKGROUND OF THE INVENTION

Cholecystokinin (CCK) is a brain-gut peptide hormone located both in thegastrointestinal system and in the central nervous system. The actionsof CCK are mediated by two G-protein coupled receptors: CCK-1 (formerlyCCK-A) and CCK-2 (formerly CCK-B/gastrin). These CCK receptors areexpressed throughout the gastrointestinal system and in different partsof the central nervous system including the cortex, the striatum, thehypothalamus, the hippocampus, the olfactory bulb, the vagal afferentneurones, in different enteric nerves and in the genital tract.

CCK has a number of biological actions. CCK is the primary hormonalregulator of gall bladder contraction in response to a meal. CCKstimulates pancreatic and biliary secretions and regulates GI motilityand specifically gut and colonic motility. CCK promotes proteinsynthesis and cell growth, especially in the GI system and in thepancreas. CCK is involved in mediating satiety after a meal. CCK is animportant neuromodulator and neurotransmitter involved in anxiety andpanic disorder. CCK modulates the release of dopamine. CCK is also knownto antagonize morphine and beta-endorphin induced analgesia and theaction on nociception. A review of CCK receptors, ligands and theactivities thereof may be found in P. Tullio et al., Exp. Opin. Invest.Drugs (2000) 9(1), pp 129-146.

A number of CCK-1 receptor antagonists are presently in clinical trialsincluding, tarazepide, devazepide and lintitript. Phase III equivalenttrials are in progress by Rotta Research Group and Forest Laboratorieson dexloxiglumide, a CCK-1 antagonist for the treatment of constipation,irritable bowel syndrome and non-ulcer dyspepsia.

Also, Kaken Pharmaceuticals and Mitsubishi-Tokyo Pharmaceuticals areawaiting registration in Japan on loxiglumide, a CCK-1 receptorantagonist for the treatment of GI cancers and pancreatitis. Loxiglumideis the racemate of dexloxiglumide.

A number of CCK-1 receptor agonists are under preclinical investigation.Glaxo Smith Kline, Inc is investigating GW 5823, GW 7854, GW 7178 and GW8573, 1,5-benzodiaepines for the treatment of gallstones,gastrointestinal disease and obesity.

Also, Pfizer is investigating the CCK-1 receptor agonist, PD 170292, for15 obesity.

In U.S. Pat. Nos. 4,826,868 and 5,164,381 there are disclosed certainpyrazoles for alleviating inflammation and treating cardiovasculardisorders in mammals having the general formula:

These compounds are not taught to be CCK-1 receptor modulators norsuggested to be useful in the treatment of disease states mediated byCCK-1 receptor activity.

In U.S. Pat. No. 5,051,518 there are disclosed certain pyrazoles foralleviating inflammation and treating cardiovascular disorders inmammals having the general formula:

These compounds are not taught to be CCK-1 receptor modulators norsuggested to be useful in the treatment of disease states mediated byCCK-1 receptor activity.

Applicants have now discovered that certain pyrazoles as described beloware useful CCK-1 receptor modulators, agonists and antagonists, and mostparticularly antagonists. As such, these compounds are useful to treat anumber of disease states mediated by CCK.

SUMMARY OF THE INVENTION

There are provided by the present invention CCK-1 receptor antagonistswhich have the general formula:

wherein,

-   -   R¹ is a 1- or 2-position substituent selected from the group        consisting of hydrogen,        -   a) phenyl, optionally mono-, di- or tri-substituted with            R^(p) or di-substituted on adjacent carbons with            —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—, —(CH₂)₁₋₂NH(CH₂)—,            —(CH₂)₂₋₃N(C₁₋₄alkyl)- or —(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—;            -   R^(p) is selected from the group consisting of —OH,                —C₁₋₆alkyl, —OC₁₋₆alkyl, phenyl, —Ophenyl, benzyl,                —Obenzyl, —C₃₋₆cycloalkyl, —OC₃₋₆cycloalkyl, —CN, —NO₂,                —N(R^(y))R^(z) (wherein R^(y) and R^(z) are                independently selected from H, C₁₋₆alkyl or C₁₋₆alkenyl,                or R^(y) and R^(z) may be taken together with the                nitrogen of attachment to form an otherwise aliphatic                hydrocarbon ring, said ring having 4 to 7 members,                optionally having one carbon replaced with >O, ═N—, >NH                or >N(C₁₋₄alkyl), optionally having one carbon                substituted with —OH, and optionally having one or two                unsaturated bonds in the ring), —(C═O)N(R^(y))R^(z),                —(N—R^(t))COR^(t), —(N—R^(t))SO₂C₁₋₆alkyl (wherein R^(t)                is H or C₁₋₆alkyl or two R^(t) in the same substituent                may be taken together with the amide of attachment to                form an otherwise aliphatic hydrocarbon ring, said ring                having 4 to 6 members), —(C═O)C₁₋₆alkyl,                —(S═(O)_(n))—C₁₋₆alkyl (wherein n is selected from 0, 1                or 2), —SO₂N(R^(y))R^(z), —SCF₃, halo, —CF₃, —OCF₃,                —COOH and —COOC₁₋₆alkyl;        -   b) phenyl or pyridyl fused at two adjacent ring members to a            three membered hydrocarbon moiety to form a fused five            membered aromatic ring, which moiety has one carbon atom            replaced by >O, >S, >NH or >N(C₁₋₄alkyl) and which moiety            has up to one additional carbon atom optionally replaced by            N, the fused rings optionally mono-, di- or tri-substituted            with R^(p);        -   c) phenyl fused at two adjacent ring members to a four            membered hydrocarbon moiety to form a fused six membered            aromatic ring, which moiety has one or two carbon atoms            replaced by N, the fused rings optionally mono-, di- or            tri-substituted with R^(p);        -   d) naphthyl, optionally mono-, di- or tri-substituted with            R^(p);        -   e) a monocyclic aromatic hydrocarbon group having five ring            atoms, having a carbon atom which is the point of            attachment, having one carbon atom replaced by >O, >S, >NH            or >N(C₁₋₄alkyl), having up to two additional carbon atoms            optionally replaced by N, optionally mono- or di-substituted            with R^(p) and optionally benzo fused on the condition that            two or fewer of said carbon ring atoms are replaced by a            heteroatom, where the benzo fused moiety is optionally mono-            di- or tri-substituted with R^(p);        -   f) a monocyclic aromatic hydrocarbon group having six ring            atoms, having a carbon atom which is the point of            attachment, having one or two carbon atoms replaced by N,            having one N optionally oxidized to the N-oxide, optionally            mono- or di-substituted with R^(p) and optionally benzo            fused, where the benzo fused moiety is optionally mono- or            di-substituted with R^(p);        -   g) adamantanyl or monocyclic C₅₋₇cycloalkyl, optionally            having one or two carbon members optionally replaced            with >O, >NH or >N(C₁₋₄alkyl) and optionally having one or            two unsaturated bonds in the ring and optionally having one            of the ring atoms substituted with —OH, ═O or —CH₃;        -   h) a C₁₋₈alkyl;        -   i) C₁₋₄alkyl, mono-substituted by a substituent selected            from the group consisting of any one of a) to g);    -   R² is selected from the group consisting of:        -   i) phenyl, optionally mono-, di- or tri- substituted with            R^(q) or di-substituted on adjacent carbons with            —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—, —(CH₂)₁₋₂NH(CH₂)—,            —(CH₂)₂₋₃N(C₁₋₄alkyl)- or —(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—;            -   R^(q) is selected from the group consisting of —OH,                —C₁₋₆alkyl, —OC₁₋₆alkyl, phenyl, —Ophenyl, benzyl,                —Obenzyl, —C₃₋₆cycloalkyl, —OC₃₋₆cycloalkyl, —CN, —NO₂,                —N(R^(y))R^(z) (wherein R^(y) and R^(z) are                independently selected from H, C₁₋₆alkyl, C₁₋₆alkenyl,                or R^(y) and R^(z) may be taken together with the                nitrogen of attachment to form an otherwise aliphatic                hydrocarbon ring, said ring having 4 to 7 members,                optionally having one carbon replaced with >O, ═N—, >NH                or >N(C₁₋₄alkyl), optionally having one carbon                substituted with —OH, and optionally having one or two                unsaturated bonds in the ring, —(C═O)N(R^(y))R^(z),                —(N—R^(t))COR^(t), —(N—R^(t))SO₂C₁₋₆alkyl (wherein R^(t)                is H or C₁₋₆alkyl or two R^(t) in the same substituent                may be taken together with the amide of attachment to                form an otherwise aliphatic hydrocarbon ring, said ring                having 4 to 6 members), —(C═O)C₁₋₆alkyl,                —(S═(O)_(n))—C₁₋₆alkyl (wherein n is selected from 0, 1                or 2), —SO₂N(R^(y))R^(z), —SCF₃, halo, —CF₃, —OCF₃,                —COOH and —COOC₁₋₆alkyl;        -   ii) phenyl or pyridyl fused at two adjacent ring members to            a three membered hydrocarbon moiety to form a fused five            membered aromatic ring, which moiety has one carbon atom            replaced by >O, >S, >NH or >N(C₁₋₄alkyl) and which moiety            has up to one additional carbon atom optionally replaced by            N, the fused rings optionally mono-, di- or tri-substituted            with R^(q);        -   iii) phenyl fused at two adjacent ring members to a four            membered hydrocarbon moiety to form a fused six membered            aromatic ring, which moiety has one or two carbon atoms            replaced by N, the fused rings optionally mono-, di- or            tri-substituted with R^(q);        -   iv) naphthyl, optionally mono-, di- or tri-substituted with            R^(q);        -   v) a monocyclic aromatic hydrocarbon group having five ring            atoms, having a carbon atom which is the point of            attachment, having one carbon atom replaced by >O, >S, >NH            or >N(C₁₋₆alkyl), having up to one additional carbon atoms            optionally replaced by N, optionally mono- or di-substituted            with R^(q) and optionally benzo fused on the condition that            two or fewer of said carbon ring atoms are replaced by a            heteroatom, where the benzo fused moiety is optionally mono-            di- or tri-substituted with R^(q); and        -   vi) a monocyclic aromatic hydrocarbon group having six ring            atoms, having a carbon atom which is the point of            attachment, having one or two carbon atoms replaced by N,            having one N optionally oxidized to the N-oxide, optionally            mono- or di-substituted with R^(p) and optionally benzo            fused, where the benzo fused moiety is optionally mono- or            di-substituted with R^(q);    -   R³ is selected from the group consisting of H, halo, and        C₁₋₆alkyl;    -   n is selected from 0,1, or 2, with the proviso that where R⁵ is        attached through —S—, the n is 1 or 2;    -   R⁴ is selected from the group consisting of H, halo or C₁₋₆alkyl        or a covalent bond in the case where the a double bond is        present in the above structure;    -   Ar is selected from the group consisting of:        -   A) phenyl, optionally mono-, di- or tri-substituted with            R^(r) or di-substituted on adjacent carbons with            —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—, —(CH₂)₁₋₂NH(CH₂)—,            —(CH₂)₂₋₃N(C₁₋₄alkyl)- or —(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—;            -   R^(r) is selected from the group consisting of —OH,                —C₁₋₆alkyl, —OC₁₋₆alkyl, phenyl, —Ophenyl, benzyl,                —Obenzyl, —C₃₋₆cycloalkyl, —OC₃₋₆cycloalkyl, —CN, —NO₂,                —N(R^(y))R^(z) (wherein R^(y) and R^(z) are                independently selected from H, C₁₋₆alkyl or C₁₋₆alkenyl,                or R^(y) and R^(z) may be taken together with the                nitrogen of attachment to form an otherwise aliphatic                hydrocarbon ring, said ring having 4 to 7 members,                optionally having one carbon replaced with >O, ═N—, >NH                or >N(C₁₋₄alkyl), optionally having one carbon                substituted with —OH, and optionally having one or two                unsaturated bonds in the ring), —(C═O)N(R^(y))R^(z),                —(N—R^(t))COR^(t), —(N—R^(t))SO₂C₁₋₆alkyl (wherein R^(t)                is H or C₁₋₆alkyl or two R^(t) in the same substituent                may be taken together with the amide of attachment to                form an otherwise aliphatic hydrocarbon ring, said ring                having 4 to 6 members), —(C═O)C₁₋₆alkyl,                —(S═(O)_(n))—C₁₋₆alkyl (wherein n is selected from 0, 1                or 2), —SO₂N(R^(y))R^(z), —SCF₃, halo, —CF₃, —OCF₃,                —COOH and —COOC₁₋₆alkyl;        -   B) phenyl or pyridyl fused at two adjacent ring members to a            three membered hydrocarbon moiety to form a fused five            membered aromatic ring, which moiety has one carbon atom            replaced by >O, >S, >NH or >N(C₁₋₄alkyl) and which moiety            has up to one additional carbon atom optionally replaced by            N, the fused rings optionally mono-, di- or tri-substituted            with R^(r);        -   C) phenyl fused at two adjacent ring members to a four            membered hydrocarbon moiety to form a fused six membered            aromatic ring, which moiety has one or two carbon atoms            replaced by N, the fused rings optionally mono-, di- or            tri-substituted with R^(r);        -   D) naphthyl, optionally mono-, di- or tri-substituted with            R^(r);        -   E) a monocyclic aromatic hydrocarbon group having five ring            atoms, having a carbon atom which is the point of            attachment, having one carbon atom replaced by >O, >S, >NH            or >N(C₁₋₄alkyl), having up to one additional carbon atoms            optionally replaced by N, optionally mono- or di-substituted            with R^(r) and optionally benzo fused on the condition that            two or fewer of said carbon ring atoms are replaced by a            heteroatom, where the benzo fused moiety is optionally mono-            di- or tri-substituted with R^(r); and        -   F) a monocyclic aromatic hydrocarbon group having six ring            atoms, having a carbon atom which is the point of            attachment, having one or two carbon atoms replaced by N,            having one N optionally oxidized to the N-oxide, optionally            mono- or di-substituted with R^(r) and optionally benzo            fused, where the benzo fused moiety is optionally mono- or            di-substituted with R^(r);    -   R⁵ is selected from the group consisting of;        -   I) —COOR⁶, where R⁶ is selected from the group consisting of            H and —C₁₋₄alkyl,        -   II) —CONR⁷R⁸, where R⁷ and R⁸ are independently selected            from the group consisting of hydrogen, C₁₋₆alkyl and            C₃₋₆cycloalkyl optionally hydroxy substituted, or R⁷ and R⁸            may be taken together with the nitrogen of attachment to            form an otherwise aliphatic hydrocarbon ring, said ring            having 5 to 7 members, optionally having one carbon replaced            with >O, ═N—, >NH or >N(C₁₋₄alkyl) and optionally having one            or two unsaturated bonds in the ring; and        -   III) tetrazolyl, [1,2,4]triazol-3-ylsulfanyl,            [1,2,4]triazol-3-ylsulfonyl, [1,2,4]triazole-3-sulfinyl and            [1,2,3]triazol-4-ylsulfanyl, [1,2,3]triazol-4-ylsulfonyl,            [1,2,3]triazol-4-sulfinyl.            and enantiomers, diastereomers and pharmaceutically            acceptable salts and esters thereof.

DETAILED DESCRIPTION OF THE INVENTION

Considering the above referenced U.S. Pat. No. 5,051,518, columns 20 and21, Applicant's invention does not include compounds of the followingformula, and/or racemic mixtures of such compounds and/or pharmaceuticalcompositions containing such compounds or racemic mixtures thereof:

where R^(q) Ar and R⁶ are selected concurrently from the groupsconsisting of: CP# R^(q) Ar R⁶ R1 —Cl phenyl- —CH₂CH₃ R2 —Cl 3,4-diMeO-—CH₂CH₃ phenyl R3 —Cl 4-MeO-phenyl- —CH₂CH₃ R4 —CH₃ 2-naphthyl- —CH₂CH₃R5 —CH₃ 1-naphthyl- —CH₂CH₃ R6 —CH₃ 2-MeO-phenyl- —CH₂CH₃ R7 —CH₃2-pyridyl- —CH₂CH₃ R8 —CH₃ 2-carboxymethyl- —CH₂CH₃ phenyl- R9 —CH₃3-pyridyl- —CH₂CH₃ R10 —Cl 4-MeO-phenyl- —H R11 —Cl 3,4-diMeO- —H phenylR12 —CH₃ 2-naphthyl- —H R13 —CH₃ 1-naphthyl- —H R14 —CH₃ 2-MeO-phenyl-—H R15 —CH₃ 2-carboxy-phenyl- —H R16 —CH₃ 4-biphenyl —CH₂CH₃ R17 —CH₃4-biphenyl —HThe instant invention does include the use of such compounds and/orracemic mixtures thereof and/or pharmaceutical compositions containingsuch compounds or racemic mixtures thereof to treat patients (humans andother mammals) with disorders related to the modulation of the CCK-1receptor. The instant invention also includes methods of making suchcompounds and/or racemic mixtures thereof.

Preferably R¹, optionally substituted with R^(p) as described above, isselected from the group consisting of hydrogen:

-   -   a) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-,        7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-,        7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4, 5, 6 or 7-yl,        1,2,3,4-tetrahydro-isoquinolin-4, 5, 6 or 7-yl,    -   b) 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or        7-benzothiophenyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or        7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl, 4-, 5-, 6- or        7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl,        imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl, pyrazolo[1,5-a]pyridin-4,        5, 6 or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl,        1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl,        1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl,        1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl,    -   c) 5-, 6-, 7- or 8-isoquinolinyl, 5-, 6-, 7- or 8-quinolinyl,        5-, 6-, 7- or 8-quinoxalinyl, 5-, 6-, 7- or 8-quinazolinyl,    -   d) naphthyl,    -   e) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl,        1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,        thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl,        pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-indoxazinyl,        2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or 3-benzofuranyl,        2- or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl, 3-indazolyl,    -   f) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl,        pyridazinyl, 1-, 3- or 4-isoquinolinyl, 2-, 3- or 4-quinolinyl,        2- or 3-quinoxalinyl, 2- or 4-quinazolinyl, 1-oxy-pyridin-2, 3,        or 4-yl,    -   g) cyclopentyl, cyclohexyl, cycloheptyl, piperidin-2,3 or 4-yl,        2-pyrrolin-2, 3, 4 or 5-yl, 3-pyrrolin-2 or 3-yl, 2-pyrazolin-3,        4 or 5-yl, morpholin-2, 3, 5 or 6-yl, thiomorpholin-2, 3, 5 or        6-yl, piperazin-2, 3, 5 or 6-yl, pyrrolidin-2 or 3-yl,        homopiperidinyl, adamantanyl,    -   h) methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl,        n-pentyl, pent-2-yl, hexyl, hex-2-yl, and    -   i) —C₁₋₂alkyl mono-substituted with any one of the preferred        substituents of a) to g).

Most preferably R¹, optionally substituted with R^(p) as describedabove, is selected from the group consisting of H, methyl, phenyl,benzyl, cyclohexyl, cyclohexylmethyl, pyridinyl, pyridinylmethyl andpyridinyl-N-oxide. Specific R¹ are selected from the group consisting ofphenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl,2,3-dimethoxy-phenyl, 3,4-dimethyoxy-phenyl, 2-chloro-phenyl,3-chloro-phenyl, 4-chloro-phenyl, 2,4-dicloro-phenyl,3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2,5-dimethyl-phenyl,2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl,4-trifluoromethyl-phenyl, 3-trifluoromethoxy-phenyl,4-trifluoromethoxy-phenyl, 4-t-butyl-phenyl, benzyl, cyclohexyl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 4-triflouromethyl-2-pyridyl,2-pyridyl-N-oxide, 4-methanesulfonyl-phenyl, 4-phenoxy-phenyl,4-isopropyl-phenyl, 4-ethoxy-phenyl, 4-hydroxy-phenyl,4-pyridinyl-methyl, benzo[1,3]diox-5-yl, 2,3-diydrobenzo[1,4]dioxin-6-yl and cyclohexylmethyl.

Preferably R^(p) is selected from the group consisting of —OH, —CH₃,—CH₂CH₃, i-propyl, t-butyl, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, —Ocyclopentyl, —Ocyclohexyl,phenyl, —Ophenyl, benzyl, —Obenzyl, —CN, —NO₂, —C(O)NH₂, —C(O)N(CH₃)₂,—C(O)NH(CH₃), —NH(CO)H, —NHCOCH₃, —NCH₃(CO)H, —NCH₃COCH₃, —NHSO₂CH₃,—NCH₃SO₂CH₃, —C(O)CH₃, —SOCH₃, —SO₂CH₃, —SO₂NH₂, —SO₂NHCH₃, —SO₂N(CH₃)₂,—SCF₃—F, —Cl, —Br, I, —CF₃, —OCF₃, —COOH, —COOCH₃, —COOCH₂CH₃, —NH₂,—NHCH₃, —NHCH₂CH₃, —NH(CH₂CH₂CH₃), —NH(CH(CH₃)CH₂CH₃), —NH(allyl),—NH(CH₂(CH₃)₂), —N(CH₃)₂, —N(CH₂CH₃)₂, —NCH₃(CH₂CH₂CH₃), —NCH₃(CH₂CH₃),—NCH₃(CH(CH₃)₂), pyrrolidin-2-one-1-yl, azetidinyl, piperidin-1-yl, 2-or 3-pyrrolin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl,pyrrolidin-1-yl, homopiperidin-1-yl.

Most preferably R^(p) is selected from the group consisting of hydrogen,methyl, methoxy, ethoxy, chloro, fluoro, trifluoromethyl,trifluoromethoxy, t-butyl, methanesulfonyl, phenoxy, isopropyl andhydroxy. Preferably R², optionally substituted with R¹ as describedabove, is selected from the group consisting of:

-   -   i) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-,        7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-,        7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4, 5, 6 or 7-yl,        1,2,3,4-tetrahydro-isoquinolin-4, 5, 6 or 7-yl,    -   ii) 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or        7-benzothiophenyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or        7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl, 4-, 5-, 6or        7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl,        imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl, pyrazolo[1,5-a]pyridin-4,        5, 6 or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl,        1H-pyrrolo[3,2-pyridin-4, 6 or 7-yl, 1H-pyrrolo[2,3-c]pyridin-4,        5 or 7-yl, 1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl,    -   iii) 5-, 6-, 7- or 8-isoquinolinyl, 5-, 6-, 7- or 8-quinolinyl,        5-, 6-, 7- or 8-quinoxalinyl, 5-, 6-, 7- or 8-quinazolinyl,    -   iv) naphthyl,    -   v) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl,        1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,        thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl,        pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-indoxazinyl,        2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or 3-benzofuranyl,        2- or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl, 3-indazolyl,        and    -   vi) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl,        pyridazinyl, 1-, 3- or 4-isoquinolinyl, 2-, 3- or 4-quinolinyl,        2- or 3-quinoxalinyl, 2- or 4-quinazolinyl,

Most preferably R², optionally substituted with R^(q) as describedabove, is selected from the group consisting of phenyl, naphthalenyl,pyridinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl,indolinyl, isoquinolinyl and quinolinyl. Specific R² are selected fromthe group consisting of 4-methyl-phenyl, 2-chloro-phenyl,3-chloro-phenyl, 4-chloro-phenyl, 3,4-dichloro-phenyl,benzo[1,3]dioxol-5-yl, 2,3-diydro benzo[1,4]dioxin-6-yl,4-methoxy-phenyl, phenyl, 4-phenoxy-phenyl, naphthalen-2-yl,pyridin-3-yl, 2-chloro-pyridin-3-yl, pyridin-4-yl methyl,4-benzyloxy-phenyl, 4-dimethylamino-phenyl, 4-bromo-3-methyl-phenyl,3-methoxy-4-methyl-phenyl, 3-cyclopentyloxy-4-methoxy-phenyl,4-bromo-2-chloro-phenyl, 4-bromo-phenyl, 3-dimethylamino-phenyl,4-morpholin-1-yl-phenyl, 4-pyrrolidin-1-yl-phenyl,4-(N-propylamino)-phenyl, 4-(N-isobutylamino)-phenyl,4-diethylamino-phenyl, 4-(N-allylamino)-phenyl,4-(N-isopropylamino)-phenyl, 4-(N-methyl-N-propylamino)-phenyl,4-(N-methyl-N-isopropylamino)-phenyl, 4-(N-methyl-N-ethylamino)-phenyl,4-amino-phenyl, 4-(N-methyl-N-propylamino)-2-chloro-phenyl,4-(N-ethyl-N-methylamino)-2-chloro-phenyl,4-pyrrolidin-1-yl)-2-chloro-phenyl, 4-azetidinyl-phenyl,4-(pyrrolidin-2-one-1-yl)-phenyl, 4-bromo-3-methyl-phenyl,4-chloro-3-methyl-phenyl, 1-methyl-5-indolinyl, 5-indolinyl,5-isoquinolinyl, 6-quinolinyl, benzo[1,3]diox-5-yl and7-methoxy-benzofuran-2-yl.

Preferably R^(q) is selected from the group consisting of —OH, —CH₃,—CH₂CH₃, i-propyl, t-butyl, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, —Ocyclopentyl, —Ocyclohexyl,phenyl, —Ophenyl, benzyl, —Obenzyl, —CN, —NO₂, —C(O)NH₂, —C(O)N(CH₃)₂,—C(O)NH(CH₃), —NH(CO)H, —NHCOCH₃, —NCH₃(CO)H, —NCH₃COCH₃, —NHSO₂CH₃,—NCH₃SO₂CH₃, —C(O)CH₃, —SOCH₃, —SO₂CH₃, —SO₂NH₂, —SO₂NHCH₃, —SO₂N(CH₃)₂,—SCF₃—F, —Cl, —Br, I, —CF₃, —OCF₃, —COOH, —COOCH₃, —COOCH₂CH₃, —NH₂,—NHCH₃, —NHCH₂CH₃, —NH(CH₂CH₂CH₃), —NH(CH(CH₃)CH₂CH₃), —NH(allyl),—NH(CH₂(CH₃)₂), —N(CH₃)₂, —N(CH₂CH₃)₂, —NCH₃(CH₂CH₂CH₃), —NCH₃(CH₂CH₃),—NCH₃(CH(CH₃)₂), pyrrolidin-2-one-1-yl, azetidinyl, piperidin-1-yl, 2-or 3-pyrrolin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl,pyrrolidin-1-yl, homopiperidin-1-yl.

Most preferably R^(q) is selected from the group consisting of methyl,bromo, chloro, methoxy, cyclopentyloxy, phenoxy, benzyloxy,pyrrolidinyl, N-methyl-N-ethylamino and dimethylamino. Preferably, thereare 0, 1 or 2 R^(q) substituents.

Preferably R³ is selected from the group consisting of —H, —F, Cl, Brand —CH₃.

Most preferably R³ is H.

Preferably n is 0, or 1.

Preferably R⁴ is selected from the group consisting of —H, —F and —CH₃.

Most preferably R⁴ is H.

In one preferred embodiment of the invention, the Ar attached carbon issaturated and has the configuration

In another preferred embodiment of the present invention, the Arattached carbon is unsaturated and has the configuration

Preferably Ar, optionally substituted with R^(r) as described above, isselected from the group consisting of:

-   -   A) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-,        7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-,        7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4, 5, 6 or 7-yl,        1,2,3,4-tetrahydro-isoquinolin-4, 5, 6 or 7-yl,    -   B) 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or        7-benzothiophenyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or        7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl, 4-, 5-, 6- or        7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl,        imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl, pyrazolo[1,5-a]pyridin-4,        5, 6 or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl,        1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl,        1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl,        1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl,    -   C) 5-, 6-, 7- or 8-isoquinolinyl, 5-, 6-, 7- or 8-quinolinyl,        5-, 6-, 7- or 8-quinoxalinyl, 5-, 6-, 7- or 8-quinazolinyl,    -   D) naphthyl,    -   E) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl,        1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,        thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl,        pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-indoxazinyl,        2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or 3-benzofuranyl,        2- or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl, 3-indazolyl,        and    -   F) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl,        pyridazinyl, 1-, 3- or 4-isoquinolinyl, 2-, 3- or 4-quinolinyl,        2- or 3-quinoxalinyl, 2- or 4-quinazolinyl.

Most preferably Ar, optionally substituted with R^(r) as describedabove, is selected from the group consisting of phenyl, naphthalenyl,benzofuran-3-yl, 4, 5, 6 or 7-benzothiophenyl, 4, 5, 6 or7-benzo[1,3]dioxolyl, 8-quinolinyl, 2-indolyl, 3-indolyl and pyridinyl.Specific Ar are selected from the group consisting of phenyl,2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2,5-dimethyl-phenyl,2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl,2-fluoro-3-trifluoromethyl-phenyl, 2-fluoro-phenyl, 2,3-difluoro-phenyl,2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2,3-dicloro-phenyl,3,4-dichlorophenyl, 2,6-dichlorophenyl, 3-iodo-phenyl,2-chloro-4-fluoro-phenyl, benzofuran-3-yl, 2-methoxy-phenyl,3-methoxy-phenyl, 4-methoxy-phenyl, 2,3-dimethoxy-phenyl,3-trifluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-ethoxy-phenyl,3-trifluoromethylsulfanyl-phenyl, naphthalen-1-yl, naphthalen-2-yl,benzo[b]thiophen-4-yl, 3-nitro-phenyl, benzo[1,3]dioxol-5-yl,pyridin-3-yl and pyridin-4-yl, 3-indolyl, 1-methyl-indol-3-yl,4-biphenyl, 3,5-dimethyl-phenyl, 3-isopropoxy-phenyl,3-dimethylamino-phenyl, 2-flouro-5-methyl-phenyl,2-methyl-3-triflouromethyl-phenyl. Preferably, there are 0, 1 or 2 R^(r)substituents.

Preferably R^(r) is selected from the group consisting of —OH, —CH₃,—CH₂CH₃, -propyl, -t-butyl, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, —Ocyclopentyl, —Ocyclohexyl,phenyl, —Ophenyl, benzyl, —Obenzyl, —CN, —NO₂, —C(O)NH₂, —C(O)N(CH₃)₂,—C(O)NH(CH₃), —NH(CO)H, —NHCOCH₃, —NCH₃(CO)H, —NCH₃COCH₃, —NHSO₂CH₃,—NCH₃SO₂CH₃, —C(O)CH₃, —SOCH₃, —SO₂CH₃, —SO₂NH₂, —SO₂NHCH₃, —SO₂N(CH₃)₂,—SCF₃, —F, —Cl, —Br, I, —CF₃, —OCF₃, —COOH, —COOCH₃, —COOCH₂CH₃, —NH₂,—NHCH₃, —NHCH₂CH₃, —NH(CH₂CH₂CH₃), —NH(CH(CH₃)CH₂CH₃), —NH(allyl),—NH(CH₂(CH₃)₂), —N(CH₃)₂, —N(CH₂CH₃)₂, —NCH₃(CH₂CH₂CH₃), —NCH₃(CH₂CH₃),—NCH₃(CH(CH₃)₂), pyrrolin-2-one-1-yl, azetidinyl, piperidin-1-yl, 2- or3-pyrrolin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl,pyrrolidin-1-yl, homopiperidin-1-yl.

Most preferably R^(r) is selected from the group consisting of methyl,methoxy, ethoxy, isopropoxy, dimethylamino, fluoro, chloro, iodo,trifluoromethyl, trifluoromethoxy, nitro, phenyl andtrifluoromethylsulfanyl.

Preferably R⁵ is selected from the group consisting of:

-   -   I) —COOH, —COOCH₃, —COOCH₂CH₃,    -   II) —CONH(CH₃), —CONH(CH₂CH₃), —CONH(CH₂CH₂CH₃),        —CONH(CH(CH₃)₂), —CONH(CH₂CH₂CH₂CH₃), —CONH(CH(CH₃)CH₂CH₃),        —CONH(C(CH₃)₃), —CONH(cyclohexyl), —CONH(2-hydroxy-cyclohexyl),        —CON(CH₃)₂, —CONCH₃(CH₂CH₃), —CONCH₃(CH₂CH₂CH₃),        —CONCH₃(CH(CH₃)₂), —CONCH₃(CH₂CH₂CH₂CH₃),        —CONCH₃(CH(CH₃)CH₂CH₃), —CONCH₃(C(CH₃)₃), —CON(CH₂CH₃)₂,        —CO-piperidin-1-yl, —CO-morpholin-4-yl, —CO-piperazin-1-yl,        —CO-imidazolidin-1-yl, —CO-pyrrolidin-1-yl, —CO-2-pyrrolin-1-yl,        —CO-3-pyrrolin-1-yl, —CO-2-imidazolin-1-yl, —CO-piperidin-1-yl,        and    -   III) -tetrazolyl, 1H-[1,2,4]triazol-5-ylsulfinyl,        1H-[1,2,4]triazol-5-ylsulfonyl, 1H-[1,2,4]triazol-5-ylsulfanyl,

Most preferably R⁵ is selected from the group consisting of —COOH andtetrazol-5-yl.

The “pharmaceutically acceptable salts and esters thereof” refer tothose salt and ester forms of the compounds of the present inventionwhich would be apparent to the pharmaceutical chemist, i.e., those whichare non-toxic and which would favorably affect the pharmacokineticproperties of said compounds of the present invention. Those compoundshaving favorable pharmacokinetic properties would be apparent to thepharmaceutical chemist, i.e., those which are non-toxic and whichpossess such pharmacokinetic properties to provide sufficientpalatability, absorption, distribution, metabolism and excretion. Otherfactors, more practical in nature, which are also important in theselection, are cost of raw materials, ease of crystallization, yield,stability, hygroscopicity and flowability of the resulting bulk drug. Inaddition, acceptable salts of carboxylates include sodium, potassium,calcium and magnesium. Examples of suitable cationic salts includehydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic,fumaric, malic, tartatic, citric, benzoic, mandelic, methanesulfonic,hydroethanesulfonic, benzenesulfonic, oxalic, palmoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic andsaccharic. Examples of suitable esters include such esters where one ormore carboxyl substituents is replaced with p-methoxybenzyloxycarbonyl,2,4,6-trimethylbenzyloxycarbonyl, 9-anthryloxycarbonyl, CH₃SCH₂COO—,tetrahydrofur-2-yloxycarbonyl, tetrahydropyran-2-yloxycarbonyl,fur-2-uloxycarbonyl, benzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl,4-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, t-butyloxycarbonyl, t-amyloxycarbonyl,diphenylmethoxycarbonyl, triphenylmethoxycarbonyl, adamantyloxycarbonyl,2-benzyloxyphenyloxycarbonyl, 4-methylthiophenyloxycarbonyl, ortetrahydropyran-2-yloxycarbonyl.

Preferred compounds of Table 1a, which were made according to thesynthetic methods outlined in Scheme A and as described in Method 2, aregiven by the formula:

where R², R¹ and Ar are selected concurrently from the groups consistingof: TABLE 1a EX R² R¹ Ar [M + H]⁺ 1 (3,4-Dichloro- (4-Methoxy-(3-Methyl-phenyl)- 481.1 phenyl)- phenyl)- [(S) enantiomer, Na⁺ salt] 2(3,4-Dichloro- (4-Methoxy- (3-Methyl-phenyl)- 481.1 phenyl)- phenyl)- 3(3,4-Dichloro- (4-Methoxy- (3-Methyl-phenyl)- 481.1 phenyl)- phenyl)-[(R) enantiomer] 4 (3,4-Dichloro- (4-Methoxy- (3-Methyl-phenyl)- 481.1phenyl)- phenyl)- [(S) enantiomer, TFA salt] 5 (4-Methyl-phenyl)-(4-Methoxy- (4-Methoxy-phenyl)- 443.2 phenyl)- 6 (4-Methyl-phenyl)-(4-Methoxy- (3-Methoxy-phenyl)- 443.2 phenyl)- 7 (4-Methyl-phenyl)-(4-Methoxy- (3-Chloro-phenyl)- 447.2 phenyl)- 8 (4-Methyl-phenyl)-(4-Methoxy- (4-Methyl-phenyl)- 427.2 phenyl)- 9 (4-Methyl-phenyl)-(4-Methoxy- (4-Chloro-phenyl)- 447.2 phenyl)- 10 (2-Chloro-phenyl)-(4-Methoxy- Naphthalen-1-yl- 483.1 phenyl)- 11 (2-Chloro-phenyl)-(4-Methoxy- (3-Chloro-phenyl)- 467.1 phenyl)- 12 (3,4-Dichloro-(4-Methoxy- Phenyl- 467.1 phenyl)- phenyl)- 13 Benzo[1,3]dioxol-(4-Methoxy- (3-Methoxy-phenyl)- 473.2 5-yl- phenyl)- 15 Phenyl-(4-Methoxy- Naphthalen-2-yl- 449.2 phenyl)- 16 (4-Phenoxy- (4-Methoxy-(3-Nitro-phenyl)- 536.2 phenyl)- phenyl)- 17 Benzo[1,3]dioxol-(4-Methoxy- Benzo[1,3]dioxol-5- 487.2 5-yl- phenyl)- yl- 18(3,4-Dichloro- (4-Methoxy- (2,3-Difluoro- 503.1 phenyl)- phenyl)-phenyl)- 19 (3,4-Dichloro- (4-Methoxy- (2-Trifluoromethyl- 535.1phenyl)- phenyl)- phenyl)- 20 (3,4-Dichloro- (4-Methoxy-(3-Ethoxy-phenyl)- 511.1 phenyl)- phenyl)- 21 (4-Methyl-phenyl)-(3,4-Dichloro- (2-Fluoro-3- 537.1 phenyl)- trifluoromethyl- phenyl)- 22(4-Phenoxy- (4-Methoxy- (4-Trifluoromethoxy- 575.2 phenyl)- phenyl)-phenyl)- 23 Benzo[1,3]dioxol- (4-Methoxy- (3-Trifluoromethoxy- 527.15-yl- phenyl)- phenyl)- 24 (4-Methyl-phenyl)- (3,4-Dichloro-(3-lodo-phenyl)- 577.0 phenyl)- 25 (4-Methyl-phenyl)- (3,4-Dichloro-(3,5-Dimethyl- 479.1 phenyl)- phenyl)- 26 (4-Methyl-phenyl)-(3,4-Dichloro- (3-Trifluoromethyl- 551.0 phenyl)- sulfanyl-phenyl)- 27Benzo[1,3]dioxol- (4-Methoxy- Naphthalen-1-yl- 493.2 5-yl- phenyl)- 28Benzo[1,3]dioxol- (4-Methoxy- Naphthalen-1-yl- 493.2 5-yl- phenyl)- [(R)enantiomer] 29 Benzo[1,3]dioxol- (4-Methoxy- Naphthalen-1-yl- 493.25-yl- phenyl)- [(S) enantiomer] 30 (4-Methoxy- (4-Methoxy-(3-Methoxy-phenyl)- 459.2 phenyl)- phenyl)- 31 (4-Methoxy- (4-Methoxy-(3-Methoxy-phenyl)- 459.2 phenyl)- phenyl)- [(R) enantiomer] 32(4-Methoxy- (4-Methoxy- (3-Methoxy-phenyl)- 459.2 phenyl)- phenyl)- [(S)enantiomer] 33 (4-Chloro-phenyl)- (4-Methoxy- Biphenyl-4-yl- 509.2phenyl)- 34 (4-Chloro-phenyl)- (4-Methoxy- (4-Methyl-phenyl)- 447.2phenyl)- 35 (4-Chloro-phenyl)- (4-Methoxy- (3-Methyl-phenyl)- 447.1phenyl)- 36 (4-Chloro-phenyl)- (4-Methoxy- (3-Methoxy-phenyl)- 463.1phenyl)- 37 (4-Chloro-phenyl)- (4-Methoxy- (3-Chloro-phenyl)- 467.2phenyl)- 38 (4-Methyl-phenyl)- (4-Chloro-phenyl)- Naphthalen-1-yl- 467.139 (4-Methyl-phenyl)- (3-Chloro-phenyl)- (3-Chloro-phenyl)- 451.0 40(4-Methyl-phenyl)- (4-Methyl-phenyl)- (3-Methyl-phenyl)- 411.1 41(4-Methyl-phenyl)- (4-Trifluoromethyl- Phenyl- 451.0 phenyl)- 42(4-Methyl-phenyl)- (3,4-Dichloro- (3-Methoxy-phenyl)- 481.0 phenyl)- 43(4-Methyl-phenyl)- Benzyl- (2-Chloro-phenyl)- 431.0 44(4-Methyl-phenyl)- Benzyl- (3-Trifluoromethyl- 465.0 phenyl)- 45(4-Methyl-phenyl)- Benzyl- Naphthalen-2-yl- 447.1 46 (4-Methyl-phenyl)-(3,4-Dichloro- (2,3-Dichloro- 519.0 phenyl)- phenyl)- 142(4-Methyl-phenyl)- (4-Methoxy- (2-Methyl-phenyl)- 427.5 phenyl)- 143(4-Methyl-phenyl)- (4-Methoxy- (2-Fluoro-phenyl)- 431.2 phenyl)- 144(4-Methyl-phenyl)- (4-Methoxy- (2,6-Dichloro- 481.1 phenyl)- phenyl)-145 (4-Methyl-phenyl)- (4-Methoxy- (3-Methoxy-phenyl)- 443.2 phenyl)-146 (4-Methyl-phenyl)- (4-Methoxy- (2,3-Dimethoxy- 473.2 phenyl)-phenyl)- 147 (4-Methyl-phenyl)- (4-Methoxy- (2-Chloro-phenyl)- 447.1phenyl)- 148 (4-Methyl-phenyl)- (4-Methoxy- (3-Methyl-phenyl)- 427.2phenyl)- 149 (4-Methyl-phenyl)- (4-Methoxy- (3,4-Dichloro- 481.1phenyl)- phenyl)- 150 (4-Methyl-phenyl)- (4-Methoxy- Phenyl- 413.2phenyl)- 151 (4-Methyl-phenyl)- (4-Methoxy- Naphthalen-1-yl- 463.2phenyl)- [(R) enantiomer] 152 (4-Methyl-phenyl)- (4-Methoxy-Naphthalen-1-yl- 463.2 phenyl)- [(S) enantiomer] 153 (4-Methyl-phenyl)-(4-Methoxy- Benzo[b]thiophen-4- 469.1 phenyl)- yl- 154(4-Methyl-phenyl)- (4-Chloro-phenyl)- (3-Chloro-phenyl)- 451.0 155(4-Methyl-phenyl)- (4-Chloro-phenyl)- (3-Methyl-phenyl)- 431.0 156(4-Methyl-phenyl)- (4-Chloro-phenyl)- Phenyl- 417.1 157(4-Methyl-phenyl)- (4-Chloro-phenyl)- (3-Methoxy-phenyl)- 447.1 158(4-Methyl-phenyl)- (4-Chloro-phenyl)- (2-Chloro-phenyl)- 451.0 159(4-Methyl-phenyl)- (4-Chloro-phenyl)- (3-Trifluoromethyl- 485.0 phenyl)-160 (4-Methyl-phenyl)- (4-Chloro-phenyl)- Naphthalen-2-yl- 467.1 161(4-Methyl-phenyl)- (3-Chloro-phenyl)- Naphthalen-1-yl- 467.1 162(4-Methyl-phenyl)- (3-Chloro-phenyl)- Phenyl- 417.1 163(4-Methyl-phenyl)- (3-Chloro-phenyl)- (3-Methoxy-phenyl)- 447.1 164(4-Methyl-phenyl)- (3-Chloro-phenyl)- (2-Chloro-phenyl)- 451.0 165(4-Methyl-phenyl)- (3-Chloro-phenyl)- (3-Trifluoromethyl- 485.0 phenyl)-166 (4-Methyl-phenyl)- (3-Chloro-phenyl)- Naphthalen-2-yl- 467.1 167(4-Methyl-phenyl)- (4-Methyl-phenyl)- Naphthalen-1-yl- 447.1 168(4-Methyl-phenyl)- (4-Methyl-phenyl)- (3-Chloro-phenyl)- 431.0 169(4-Methyl-phenyl)- (4-Methyl-phenyl)- Phenyl- 397.1 170(4-Methyl-phenyl)- (4-Methyl-phenyl)- (3-Methoxy-phenyl)- 427.1 171(4-Methyl-phenyl)- (4-Methyl-phenyl)- (2-Chloro-phenyl)- 431.0 172(4-Methyl-phenyl)- (4-Methyl-phenyl)- (3-Trifluoromethyl- 466.1 phenyl)-173 (4-Methyl-phenyl)- (4-Methyl-phenyl)- Naphthalen-2-yl- 447.1 174(4-Methyl-phenyl)- (4-Trifluoromethyl- Naphthalen-1-yl- 501.1 phenyl)-175 (4-Methyl-phenyl)- (4-Trifluoromethyl- (3-Chloro-phenyl)- 485.0phenyl)- 176 (4-Methyl-phenyl)- (4-Trifluoromethyl- (3-Methyl-phenyl)-465.1 phenyl)- 177 (4-Methyl-phenyl)- (4-Trifluoromethyl-(3-Methoxy-phenyl)- 481.1 phenyl)- 178 (4-Methyl-phenyl)-(4-Trifluoromethyl- (2-Chloro-phenyl)- 485.0 phenyl)- 179(4-Methyl-phenyl)- (4-Trifluoromethyl- (3-Trifluoromethyl- 519.1phenyl)- phenyl)- 180 (4-Methyl-phenyl)- (4-Trifluoromethyl-Naphthalen-2-yl- 501.1 phenyl)- 181 (4-Methyl-phenyl)- (3,4-Dichloro-Naphthalen-1-yl- 501.0 phenyl)- 182 (4-Methyl-phenyl)- (3,4-Dichloro-(3-Chloro-phenyl)- 485.0 phenyl)- 183 (4-Methyl-phenyl)- (3,4-Dichloro-(3-Methyl-phenyl)- 465.1 phenyl)- 184 (4-Methyl-phenyl)- (3,4-Dichloro-Phenyl- 451.0 phenyl)- 185 (4-Methyl-phenyl)- (3,4-Dichloro-(2-Chloro-phenyl)- 485.0 phenyl)- 186 (4-Methyl-phenyl)- (3,4-Dichloro-(3-Trifluoromethyl- 519.0 phenyl)- phenyl)- 187 (4-Methyl-phenyl)-(3,4-Dichloro- Naphthalen-2-yl- 501.0 phenyl)- 188 (4-Methyl-phenyl)-(3,4-Dichloro- (3-Nitro-phenyl)- 496.1 phenyl)- 189 (4-Methyl-phenyl)-(3,4-Dichloro- Benzo[1,3]dioxol-5- 495.1 phenyl)- yl- 190(4-Methyl-phenyl)- (3,4-Dichloro- Benzo[b]thiophen-4- 507.0 phenyl)- yl-191 (4-Methyl-phenyl)- (3,4-Dichloro- (2,3-Difluoro- 487.1 phenyl)-phenyl)- 192 (4-Methyl-phenyl)- (3,4-Dichloro- (2-Trifluoromethyl- 519.1phenyl)- phenyl)- 193 (4-Methyl-phenyl)- (3,4-Dichloro-(4-Trifluoromethoxy- 535.0 phenyl)- phenyl)- 194 (4-Methyl-phenyl)-(3,4-Dichloro- (3-Trifluoromethoxy- 535.1 phenyl)- phenyl)- 195(4-Methyl-phenyl)- Benzyl- Naphthalen-1-yl- 447.1 196 (4-Methyl-phenyl)-Benzyl- (3-Chloro-phenyl)- 431.0 197 (4-Methyl-phenyl)- Benzyl-(3-Methyl-phenyl)- 411.1 198 (4-Methyl-phenyl)- Benzyl- Phenyl- 398.1199 (4-Methyl-phenyl)- Benzyl- (3-Methoxy-phenyl)- 427.1 200(4-Chloro-phenyl)- (4-Methoxy- (2-Chloro-4-fluoro- 485.1 phenyl)-phenyl)- 201 (4-Chloro-phenyl)- (4-Methoxy- (2-Chloro-phenyl)- 467.1phenyl)- 202 (4-Chloro-phenyl)- (4-Methoxy- (2,6-Dichloro- 501.1phenyl)- phenyl)- 203 (4-Chloro-phenyl)- (4-Methoxy- (2-Methoxy-phenyl)-463.1 phenyl)- 204 (4-Chloro-phenyl)- (4-Methoxy- Phenyl- 433.1 phenyl)-205 (4-Chloro-phenyl)- (4-Methoxy- (2-Methyl-phenyl)- 447.1 phenyl)- 206(4-Chloro-phenyl)- (4-Methoxy- (2-Fluoro-phenyl)- 451.1 phenyl)- 207(4-Chloro-phenyl)- (4-Methoxy- Naphthalen-1-yl- 483.1 phenyl)- 208(4-Chloro-phenyl)- (4-Methoxy- Pyridin-3-yl- 434.1 phenyl)- 209(3,4-Dichloro- (4-Methoxy- (3-Chloro-phenyl)- 501.0 phenyl)- phenyl)-210 (3,4-Dichloro- (4-Methoxy- Naphthalen-1-yl- 517.1 phenyl)- phenyl)-211 (3,4-Dichloro- (4-Methoxy- (3-Methoxy-phenyl)- 497.1 phenyl)-phenyl)- 212 (3,4-Dichloro- (4-Methoxy- Naphthalen-2-yl- 517.1 phenyl)-phenyl)- 213 (3,4-Dichloro- (4-Methoxy- (3-Nitro-phenyl)- 512.1 phenyl)-phenyl)- 214 (3,4-Dichloro- (4-Methoxy- Benzo[1,3]dioxol-5- 511.1phenyl)- phenyl)- yl- 215 (3,4-Dichloro- (4-Methoxy- (2-Fluoro-3- 553.1phenyl)- phenyl)- trifluoromethyl- phenyl)- 216 (3,4-Dichloro-(4-Methoxy- (4-Trifluoromethoxy- 551.1 phenyl)- phenyl)- phenyl)- 217(3,4-Dichloro- (4-Methoxy- (3-Iodo-phenyl)- 593.0 phenyl)- phenyl)- 218(3,4-Dichloro- (4-Methoxy- (3,5-Dimethyl- 495.1 phenyl)- phenyl)-phenyl)- 219 (3,4-Dichloro- (4-Methoxy- (2,3-Dichloro- 535.0 phenyl)-phenyl)- phenyl)- 220 Benzo[1,3]dioxol- (4-Methoxy- (3-Methyl-phenyl)-457.1 5-yl- phenyl)- 221 Benzo[1,3]dioxol- (4-Methoxy-(3-Chloro-phenyl)- 477.1 5-yl- phenyl)- 222 Benzo[1,3]dioxol-(4-Methoxy- Phenyl- 443.1 5-yl- phenyl)- 223 Benzo[1,3]dioxol-(4-Methoxy- Naphthalen-2-yl- 493.1 5-yl- phenyl)- 224 Benzo[1,3]dioxol-(4-Methoxy- (3-Nitro-phenyl)- 488.1 5-yl- phenyl)- 225 Benzo[1,3]dioxol-(4-Methoxy- (2,3-Difluoro- 479.1 5-yl- phenyl)- phenyl)- 226Benzo[1,3]dioxol- (4-Methoxy- (2-Trifluoromethyl- 511.1 5-yl- phenyl)-phenyl)- 227 Benzo[1,3]dioxol- (4-Methoxy- (3-Ethoxy-phenyl)- 487.25-yl- phenyl)- 228 Benzo[1,3]dioxol- (4-Methoxy- (2-Fluoro-3- 529.15-yl- phenyl)- trifluoromethyl- phenyl)- 229 Benzo[1,3]dioxol-(4-Methoxy- (4-Trifluoromethoxy- 527.1 5-yl- phenyl)- phenyl)- 230Benzo[1,3]dioxol- (4-Methoxy- (3-Trifluoromethyl- 543.1 5-yl- phenyl)-sulfanyl-phenyl)- 231 Benzo[1,3]dioxol- (4-Methoxy- (3-Iodo-phenyl)-569.1 5-yl- phenyl)- 232 Benzo[1,3]dioxol- (4-Methoxy- (3,5-Dimethyl-471.2 5-yl- phenyl)- phenyl)- 233 Benzo[1,3]dioxol- (4-Methoxy-(2,3-Dichloro- 511.1 5-yl- phenyl)- phenyl)- 234 (4-Methoxy- (4-Methoxy-(3-Methyl-phenyl)- 443.2 phenyl)- phenyl)- 235 (4-Methoxy- (4-Methoxy-(3-Chloro-phenyl)- 463.1 phenyl)- phenyl)- 236 (4-Methoxy- (4-Methoxy-Naphthalen-1-yl- 479.2 phenyl)- phenyl)- 237 (4-Methoxy- (4-Methoxy-Naphthalen-2-yl- 479.2 phenyl)- phenyl)- 238 Phenyl- (4-Methoxy-(3-Chloro-phenyl)- 433.1 phenyl)- 239 Phenyl- (4-Methoxy-Naphthalen-1-yl- 449.2 phenyl)- 240 Phenyl- (4-Methoxy-(3-Methoxy-phenyl)- 429.2 phenyl)- 241 Phenyl- (4-Methoxy- Phenyl- 399.2phenyl)- 242 (2-Chloro-phenyl)- (4-Methoxy- (3-Methoxy-phenyl)- 463.1phenyl)- 243 (2-Chloro-phenyl)- (4-Methoxy- Phenyl- 433.1 phenyl)- 244(2-Chloro-phenyl)- (4-Methoxy- Naphthalen-2-yl- 483.1 phenyl)- 245(4-Phenoxy- (4-Methoxy- (3-Methyl-phenyl)- 505.2 phenyl)- phenyl)- 246(4-Phenoxy- (4-Methoxy- (3-Chloro-phenyl)- 525.2 phenyl)- phenyl)- 247(4-Phenoxy- (4-Methoxy- Naphthalen-1-yl- 541.2 phenyl)- phenyl)- 248(4-Phenoxy- (4-Methoxy- (3-Methoxy-phenyl)- 521.2 phenyl)- phenyl)- 249(4-Phenoxy- (4-Methoxy- Phenyl- 491.2 phenyl)- phenyl)- 250 (4-Phenoxy-(4-Methoxy- Naphthalen-2-yl- 541.2 phenyl)- phenyl)- 251 (4-Phenoxy-(4-Methoxy- Benzo[1,3]dioxol-5- 535.2 phenyl)- phenyl)- yl- 252(4-Phenoxy- (4-Methoxy- (2,3-Difluoro- 527.2 phenyl)- phenyl)- phenyl)-253 (4-Phenoxy- (4-Methoxy- (2-Trifluoromethyl- 559.2 phenyl)- phenyl)-phenyl)- 254 (4-Phenoxy- (4-Methoxy- (3-Ethoxy-phenyl)- 535.2 phenyl)-phenyl)- 255 (4-Phenoxy- (4-Methoxy- (2-Fluoro-3- 577.2 phenyl)-phenyl)- trifluoromethyl- phenyl)- 256 (4-Phenoxy- (4-Methoxy-(3-Trifluoromethoxy- 575.2 phenyl)- phenyl)- phenyl)- 257 (4-Phenoxy-(4-Methoxy- (3-Trifluoromethyl- 591.2 phenyl)- phenyl)-sulfanyl-phenyl)- 258 (4-Phenoxy- (4-Methoxy- (3-Iodo-phenyl)- 617.1phenyl)- phenyl)- 259 (4-Phenoxy- (4-Methoxy- (3,5-Dimethyl- 519.2phenyl)- phenyl)- phenyl)- 260 (4-Phenoxy- (4-Methoxy- (2,3-Dichloro-559.1 phenyl)- phenyl)- phenyl)-

Preferred compounds of Table 1b, which were made according to thesynthetic methods outlined in Schemes A, H, J and L, are given by theformula:

where R², R¹ and Ar are selected concurrently from the groups consistingof: TABLE 1b [M + H]⁺ EX R² R¹ Ar *[M − H]⁻ 77 (4-Bromo-(4-Methyl-phenyl)- (3-Methyl-phenyl)- 475/477 phenyl)- 85 (4-Bromo-2-(4-Methyl-phenyl)- (3-Methyl-phenyl)- 509/511 chloro-phenyl)- 106Quinolin-6-yl- (4-Methyl-phenyl)- (3-Methyl-phenyl)- 448.2 126(3,4-Dichloro- (4-Ethoxy-phenyl)- (3-Chloro-phenyl)- *513 phenyl)- 127Naphthalen-2-yl- (2,5-Dichloro- (3-Chloro-phenyl)- 521/523 phenyl)- 128Naphthalen-2-yl- (4-Ethoxy-phenyl)- (3-Chloro-phenyl)- 497.1 319Benzo[1,3]dioxol-5-yl- (4-Methyl-phenyl)- (3-Methyl-phenyl)- 320(4-Chloro- (4-Methoxy- 3-Isopropoxy- phenyl)- phenyl)- 321Naphthalen-2-yl- Benzyl- (3-Methyl-phenyl)- 322 Benzo[1,3]dioxol- Benzyl(3-Methyl-phenyl)- 5-yl- 323 (3,4-Dichloro- (2,4-Dichloro-(2,5-Dimethyl- phenyl)- phenyl)- phenyl)- 324 (3,4-Dichloro-(2,4-Dichloro- (3-Chloro-phenyl)- phenyl)- phenyl)- 325 (3,4-Dichloro-(2,4-Dichloro- (3-Isoproxy-phenyl)- phenyl)- phenyl)- 326 (3,4-Dichloro-(2,4-Dichloro- (2-Fluoro-5-methyl- phenyl)- phenyl)- phenyl)- 327(3,4-Dichloro- (2,4-Dichloro- (2-Methyl-3- phenyl)- phenyl)-trifluoromethyl- phenyl)- 328 (3,4-Dichloro- (4-Hydroxy-(3-Methyl-phenyl)- phenyl)- phenyl)- [(S) enantiomer] 329 (3,4-Dichloro-(4-Ethoxy-phenyl)- (3-Methyl-phenyl)- phenyl)- 330 Naphthalen-2-yl-(4-Ethoxy-phenyl)- (3-Chloro-phenyl)- 331 (3,4-Dichloro-(4-Ethoxy-phenyl)- (3-Chloro-phenyl)- phenyl)- 332 (3,4-Dichloro-(2,5-Dichloro- (3-Chloro-phenyl)- phenyl)- phenyl)- 333 (4-Chloro-(4-Methoxy- (4-Chloro-phenyl)- phenyl)- phenyl)- 334 (3,4-Dichloro-(4-Methoxy- (3- phenyl)- phenyl)- Trifluoromethylsulfanyl- phenyl)-Compound 328 was made by demethylation of Compound 1.

Preferred compounds of Table 2, which were made according to thesynthetic methods outlined in Scheme A and as described in Method 2 orExample 71, are given by the formula:

where R² and Ar are selected concurrently from the groups consisting of:TABLE 2 EX R² Ar [M + H]⁺ 14 (4-Methoxy- Benzofuran-3-yl- 469.2 phenyl)-71 (4-Methyl-phenyl)- (1H-indol-3-yl)- 452.2 72 (4-Methyl-phenyl)-(1-Methyl-1H-indol-3-yl)- 466.2 261 (3,4-Dichloro- Benzofuran-3-yl-507.1 phenyl)- 262 Benzo[1,3]dioxol-5- Benzofuran-3-yl- 483.2 yl- 263Phenyl- Benzofuran-3-yl- 439.1 264 (2-Chloro-phenyl)- Benzofuran-3-yl-473.1 265 (4-Phenoxy- Benzofuran-3-yl- 531.2 phenyl)-

Preferred compounds of Table 3a, which were made according to thesynthetic methods outlined in Schemes A, B, C, D and H, and as describedin Examples 64-68, 73 and 74, are given by the formula:

where R² and R⁵—Y— are selected concurrently from the groups consistingof: TABLE 3a EX R² R⁵—Y— [M + H]⁺ 64 (4-Methyl-phenyl)-(2-Hydroxy-cyclohexyl- 524.2 carbamoyl)- 65 (4-Methyl-phenyl)-Carbamoyl- 426.2 66 (4-Methyl-phenyl)- (Dimethyl-carbamoyl)- 454.2 67(4-Methyl-phenyl)- (Methyl-carbamoyl)- 440.2 68 (4-Methyl-phenyl)-(4-Methyl-piperazine-1- 509.2 carbonyl)-

Preferred compounds of Table 3b, which were made according to thesynthetic methods outlined in Schemes D and 1, are given by the formula:

where R² and R⁵-Y-are selected concurrently from the groups consistingof: TABLE 3b EX R² R¹ Ar R⁵—Y— [M + H]⁺ 74 (4-Methyl- (4-Methoxy-(3-Methyl- (1H-Tetrazol-5- 451.2 phenyl)- phenyl)- phenyl)- yl)- 129(3,4-Dichloro- (4-Methoxy- (3-Methyl- (1H-Tetrazol-5- 505.3 phenyl)-phenyl)- phenyl)- yl)- [(S) enantiomer] 130 (3,4-Dichloro- (4-Methoxy-(3-Methyl- (1H-Tetrazol-5- 505.1 phenyl)- phenyl)- phenyl)- yl)-[racemic] 131 (3,4-Dichloro- (4-Methoxy- (3-Methyl- (1H-Tetrazol-5-505.3 phenyl)- phenyl)- phenyl)- yl)- [(R) enantiomer] 132Benzo[1,3]dioxol- (2,5-Dichloro- (3-chloro- (1H-Tetrazol-5- 539.0 5-yl-phenyl)- phenyl)- yl)- 135 3,4-Dichloro- (4-Methoxy- (3-Methyl- (2H-550.1 phenyl- phenyl)- phenyl)- [1,2,4]Triazol-3- ylsulfanylmethyl)- 136(4-Methyl- (4-Methyl- (3-Methyl- (2H- 496.2 phenyl)- phenyl)- phenyl)-[1,2,4]Triazole-3- sulfinylmethyl)- 137 (4-Methyl- (4-Methyl- (3-Methyl-(2H- 512.2 phenyl)- phenyl)- phenyl)- [1,2,4]Triazole-3-sulfonylmethyl)- 138 3,4-Dichloro- (4-Methoxy- (3-Methyl- (2H- 582.3phenyl- phenyl)- phenyl)- [1,2,4]Triazole-3- sulfonylmethyl)- [(S)enantiomer] 335 (4-Methyl- (4-Methyl- (3-Methyl- (2H- phenyl)- phenyl)-phenyl)- [1,2,4]Triazol-3- ylsulfanylmethyl)-

Preferred compounds of Table 4, which were made according to thesynthetic methods outlined in Schemes E and F, and as described inMethods 4 and 6, are given by the formula:

where R² and R¹ are selected concurrently from the groups consisting of:TABLE 4 EX R² R¹ [M + H]⁺ 53 (4-Phenoxy-phenyl)- (4-tert-Butyl-phenyl)-531.2 54 (3,4-Dichloro-phenyl)- (4-Methanesulfonyl- 529.1 phenyl)- 55Benzo[1,3]dioxol-5-yl- (2-Chloro-phenyl)- 461.0 57 (3-Chloro-phenyl)-(2,4-Dichloro-phenyl)- 485.1 58 (4-Benzyloxy-phenyl)-(4-Trifluoromethoxy- 573.5 phenyl)- 59 (4-Dimethylamino-phenyl)-(4-Methyl-phenyl)- 440.3 60 (3-Methoxy-4-methyl- (4-Methyl-phenyl)-441.3 phenyl)- 61 (3-Cyclopentyloxy-4- (4-Methyl-phenyl)- 511.4methoxy-phenyl)- 62 (4-Bromo-3-methyl-phenyl)- (4-Phenoxy-phenyl)- 567.4266 Naphthalen-2-yl- (2,4-Dichloro-phenyl)- 501.0 267 Naphthalen-2-yl-(2-Chloro-phenyl)- 467.1 268 Naphthalen-2-yl- (4-Methanesulfonyl- 511.1phenyl)- 269 Naphthalen-2-yl- (4-tert-Butyl-phenyl)- 489.2 270Naphthalen-2-yl- (4-Trifluoromethoxy- 517.5 phenyl)- 271Naphthalen-2-yl- (4-Methyl-phenyl)- 447.3 272 Naphthalen-2-yl-(4-Phenoxy-phenyl)- 525.4 273 (3,4-Dichloro-phenyl)-(2,4-Dichloro-phenyl)- 519.0 274 (3,4-Dichloro-phenyl)-(2-Chloro-phenyl)- 485.0 275 (3,4-Dichloro-phenyl)-(4-tert-Butyl-phenyl)- 507.1 276 Benzo[1,3]dioxol-5-yl-(2,4-Dichloro-phenyl)- 495.0 277 Benzo[1,3]dioxol-5-yl-(4-Methanesulfonyl- 505.1 phenyl)- 278 Benzo[1,3]dioxol-5-yl-(4-tert-Butyl-phenyl)- 483.2 279 (3-Chloro-phenyl)- (2-Chloro-phenyl)-451.0 280 (3-Chloro-phenyl)- (4-Methanesulfonyl- 495.1 phenyl)- 281(3-Chloro-phenyl)- (4-tert-Butyl-phenyl)- 473.2 282 (4-Phenoxy-phenyl)-(2,4-Dichloro-phenyl)- 543.1 283 (4-Phenoxy-phenyl)- (2-Chloro-phenyl)-509.1 284 (4-Phenoxy-phenyl)- (4-Methanesulfonyl- 553.1 phenyl)- 285(4-Benzyloxy-phenyl)- (4-Methyl-phenyl)- 503.4 286 (4-Benzyloxy-phenyl)-(4-Phenoxy-phenyl)- 581.5 287 (4-Dimethylamino-phenyl)-(4-Trifluoromethoxy- 510.1 phenyl) 288 (4-Dimethylamino-phenyl)-(4-Phenoxy-phenyl)- 518.4 289 (4-Bromo-3-methyl-phenyl)-(4-Methyl-phenyl)- 489.3 290 (3-Methoxy-4-methyl- (4-Trifluoromethoxy-511.1 phenyl)- phenyl)- 291 (3-Methoxy-4-methyl- (4-Phenoxy-phenyl)-519.4 phenyl)- 292 (3-Cyclopentyloxy-4- (4-Trifluoromethoxy- 581.4methoxy-phenyl)- phenyl)- 293 (3-Cyclopentyloxy-4- (4-Phenoxy-phenyl)-589.5 methoxy-phenyl)- 294 (4-Chloro-3-methyl-phenyl)-(4-Isopropyl-phenyl)- 473.2

Preferred compounds of Table 5a, which were made according to thesynthetic methods outlined in Schemes E and F, and as described inMethods 4 and 6, are given by the formula:

where R² and R¹ are selected concurrently from the groups consisting of:TABLE 5a EX R² R¹ [M + H]⁺ 52 Naphthalen-2-yl- Pyridin-2-yl- 434.2 56Pyridin-3-yl- (2,4-Dichloro-phenyl)- 452.0 295 (3,4-Dichloro-phenyl)-Pyridin-2-yl- 452.1 296 Benzo[1,3]dioxol-5-yl- Pyridin-2-yl- 428.1 297(3-Chloro-phenyl)- Pyridin-2-yl- 418.1 298 (4-Phenoxy-phenyl)-Pyridin-2-yl- 476.2 299 Pyridin-3-yl- (4-tert-Butyl-phenyl)- 440.2

Preferred compounds of Table 5b, which were made according to thesynthetic methods outlined in Scheme L, and as described in Example 105,are Methods given by the formula:

where R² and R¹ are selected concurrently from the groups consisting of:TABLE 5b EX R² R¹ [M + H]⁺ 78 (4-Dimethylamino- Pyridin-2-yl- 427.2phenyl)- 80 Naphthalen-2-yl- (5-Trifluoromethyl- pyridin-2-yl)- 81(2-Chloro-pyridin-3-yl)- (2,4-Dichloro-phenyl)- 486/488 89Naphthalen-2-yl- Pyridin-4-ylmethyl- 448.3 92 Naphthalen-2-yl-Pyridin-2-yl- 434.1 [(S) enantiomer] 93 Naphthalen-2-yl- Pyridin-2-yl-434.1 [(R) enantiomer] 105 Naphthalen-2-yl- (1-Oxy-pyridin-2-yl)- 450.1337 (3,4-Dichloro-phenyl)- (5-Trifluoromethyl- pyridin-2-yl)-

Preferred compounds of Table 6, which were made according to thesynthetic methods outlined in Schemes E, F and L, and as described inMethods 4 and 6, are given by the formula:

where R² and R^(t) are selected concurrently from the groups consistingof: TABLE 6 EX R² R¹ [M + H]⁺ 47 Naphthalen-2-yl- H— 357.2 49(3,4-Dichloro-phenyl)- Methyl 388.9 51 Naphthalen-2-yl- Cyclohexyl-439.2 300 (3,4-Dichloro-phenyl)- Cyclohexyl- 457.0 301Benzo[1,3]dioxol-5-yl- Cyclohexyl- 433.3 302 (3-Chloro-phenyl)- H— 341.1303 (3-Chloro-phenyl)- Methyl 355.0 304 (3-Chloro-phenyl)- Cyclohexyl-423.2 305 (4-Phenoxy-phenyl)- H— 399.1 306 (4-Phenoxy-phenyl)-Cyclohexyl- 481.1 307 (4-Dimethylamino- Cyclohexyl- 432.4 phenyl)- 308(4-Bromo-3-methyl- Cyclohexyl- 481.4 phenyl)- 309 (3-Cyclopentyloxy-4-Cyclohexyl- 503.5 methoxy-phenyl)- 338 (3,4-Dichloro-phenyl)- H—

Preferred compounds of Table 7, which were made according to thesynthetic methods outlined in Schemes E and F, and as described inMethods 4 and 6, are given by the formula:

where R² and R¹ are selected concurrently from the groups consisting of:TABLE 7 EX R² R¹ [M + H]⁺ 63 (7-Methoxy- (4-Phenoxy-phenyl)- 545.4benzofuran-2-yl)- 310 (7-Methoxy- (4-Trifluoromethoxy- 537.3benzofuran-2-yl)- phenyl)- 311 (7-Methoxy- (4-Methyl-phenyl)- 467.4benzofuran-2-yl)- 312 (7-Methoxy- Cyclohexyl- 459.4 benzofuran-2-yl)-

Preferred compounds of Table 8a, which were made according to thesynthetic methods outlined in Schemes E and F, and as described inMethods 4 and 6, are given by the formula:

where R² and R¹ are selected concurrently from the groups consisting of:TABLE 8a EX R² R¹ [M + H]⁺ 48 (3,4-Dichloro-phenyl)- Methyl 388.9 50Naphthalen-2-yl- Cyclohexyl- 439.2 313 (4-Bromo-3-methyl- Cyclohexyl-481.4 phenyl)- 314 (3,4-Dichloro-phenyl)- Cyclohexyl- 457.0 315Benzo[1,3]dioxol-5-yl- Cyclohexyl- 433.2 316 (3-Chloro-phenyl)- Methyl355.0 317 (3-Chloro-phenyl)- Cyclohexyl- 423.1 318 (4-Phenoxy-phenyl)-Cyclohexyl- 481.1

Preferred compounds of Table 8b, which were made according to thesynthetic methods outlined in Scheme L, are given by the formula:

where R² and R¹ are selected concurrently from the groups consisting of:TABLE 8b EX R² R¹ [M + H]⁺ 79 Naphthalen-1-yl Pyridin-2-yl 434.2 82Benzo[1,3]dioxol-5-yl- Cyclohexylmethyl- 447.2 83 Naphthalen-2-yl-Benzyl- 84 (4-Dimethylamino- Benzyl- phenyl)- 88 Naphthalen-2-yl-Pyridin-4-ylmethyl- 448.3 90 (3-Dimethylamino- (4-Methyl-phenyl)- 440.3phenyl)- 339 (4-Dimethylamino- (4-Methanesulfonyl- phenyl)- phenyl)- 340Benzo[1,3]dioxol-5-yl- Benzyl- 341 (3-Dimethylamino-(2,5-Dimethyl-phenyl)- phenyl)- 342 (3-Dimethylamino-(4-Methoxy-phenyl)- phenyl)-

Preferred compounds of Table 9, which were made according to thesynthetic methods outlined in Scheme L, are given by the formula:

where R² and R¹ are selected concurrently from the groups consisting of:TABLE 9 EX R² R¹ [M + H]⁺ 86 (4-Dimethylamino- (4-Methyl-phenyl)- 440.2phenyl)- 87 (1-Methyl-2,3-dihydro- (4-Methyl-phenyl)- 452.31H-indol-5-yl)- 91 (3-Dimethylamino- (4-Methyl-phenyl)- 440.4 phenyl)-94 (4-Allylamino-phenyl)- (4-Methyl-phenyl)- 452.6 95(2-Chloro-4-pyrrolidin- (4-Methyl-phenyl)- 500.1 1-yl-phenyl)- 96(4-Diethylamino- (4-Methyl-phenyl)- 468.3 phenyl)- 97 (4-Isobutylamino-(4-Methyl-phenyl)- 468.3 phenyl)- 98 (4-Morpholin-4-yl-(4-Methyl-phenyl)- 482.2 phenyl)- 99 [2-Chloro-4-(ethyl-(4-Methyl-phenyl)- 488.1 methyl-amino)- phenyl]- 100 [4-(Ethyl-methyl-(4-Methyl-phenyl)- 454.3 amino)-phenyl]- 101 [4-(Isopropyl-methyl-(4-Methyl-phenyl)- 468.3 amino)-phenyl]- 102 (4-Acetylamino-(4-Methyl-phenyl)- 454.3 phenyl)- 103 [4-(Formyl-methyl-(4-Methyl-phenyl)- 454.3 amino)-phenyl]- 104 [4-(2-Oxo-pyrrolidin-1-(4-Methyl-phenyl)- 480.3 yl)-phenyl]- 107 (4-Amino-phenyl)-(4-Methyl-phenyl)- 412.2 344 (4-Dimethylamino- Cyclohexylmethyl-phenyl)- 345 (4-Dimethylamino- Pyridin-4-ylmethyl- phenyl)- 346(4-Dimethylamino- Benzyl- phenyl)- 347 (3-Dimethylamino-(2,5-Dimethyl-phenyl)- phenyl)- 348 (3-Dimethylamino-(4-Methoxy-phenyl)- phenyl)- 349 (4-Piperidin-1-yl- (4-Methyl-phenyl)-phenyl)- 350 [4-(Methyl-propyl- (4-Methyl-phenyl)- amino)-phenyl]- 351(4-Isopropylamino- (4-Methyl-phenyl)- phenyl)- 352 (4-Pyrrolidin-1-yl-(4-Methyl-phenyl)- phenyl)- 353 (4-Propylamino- (4-Methyl-phenyl)-phenyl)- 354 [2-Chloro-4-(methyl- (4-Methyl-phenyl)- propyl-amino)-phenyl]- 355 (4-Azetidin-1-yl- (4-Methyl-phenyl)- phenyl)- 356[4-(Acetyl-methyl- (4-Methyl-phenyl)- amino)-phenyl]-

Preferred compounds of Table 10, which were made according to thesynthetic methods outlined in Scheme H, are given by the formula:

where R², R¹ and Ar are selected concurrently from the groups consistingof: TABLE 10 [M + H]⁺ EX R² R¹ Ar *[M − H]⁻ 75 (3,4-Dichloro-phenyl)-(4-Methoxy- (3-Methyl-phenyl)- 479.0 phenyl)- [(E) stereoisomer] 108(3,4-Dichloro- (4-Ethoxy-phenyl)- (3-Chloro-phenyl)- *511/ phenyl)- [(Z)stereoisomer] 513 109 (3,4-Dichloro- (4-Ethoxy-phenyl)-(3-Chloro-phenyl)- 513 phenyl)- [(E) stereoisomer] 110 (3,4-Dichloro-Pyridin-2-yl- (3-Chloro-phenyl)- *468 phenyl)- [(Z) stereoisomer] 111(3,4-Dichloro- (2,5-Dichloro- (3-Chloro-phenyl)- *535/ phenyl)- phenyl)-[(Z) stereoisomer] 537 112 Naphthalen-2-yl- (2,5-Dichloro-(3-Chloro-phenyl)- 519/ phenyl)- [(Z) stereoisomer] 521 113Naphthalen-2-yl- (4-ethoxy-phenyl)- (3-Chloro-phenyl)- 495.1 [(Z)stereoisomer] 114 (3,4-Dichloro- (4-Methoxy- Phenyl- 465.1 phenyl)-phenyl)- [(Z) stereoisomer] 115 (3,4-Dichloro- (4-Methoxy-(3-Chloro-phenyl)- 499.0 phenyl)- phenyl)- [(Z) stereoisomer] 116(3,4-Dichloro- (4-Methoxy- (4-Chloro-phenyl)- 499.0 phenyl)- phenyl)-[(Z) stereoisomer] 117 (3,4-Dichloro- (4-Methoxy- (4-Methoxy-phenyl)-495.0 phenyl)- phenyl)- [(Z) stereoisomer] 118 (3,4-Dichloro-(4-Methoxy- (3,4-Dichloro-phenyl)- 533.0 phenyl)- phenyl)- [(Z)stereoisomer] 119 (3,4-Dichloro- (4-Methoxy- (4-Methyl-phenyl)- 479.1phenyl)- phenyl)- [(Z) stereoisomer] 120 (3,4-Dichloro- (4-Methoxy-(3-Methyl-phenyl)- 479.1 phenyl)- phenyl)- [(Z) stereoisomer] 121Benzo[1,3]dioxol-5- (4-Ethoxy-phenyl)- (3-Chloro-phenyl)- 489.1 yl- [(Z)stereoisomer] 122 Benzo[1,3]dioxol-5- (2,5-Dichloro- (3-Chloro-phenyl)-513.0 yl- phenyl)- [(Z) stereoisomer] 123 Benzo[1,3]dioxol-5-(2,5-Dichloro- (3-Chloro-phenyl)- 513 yl- phenyl)- [(E) stereoisomer]124 (3,4-Dichloro- (4-Methoxy- (3,4-Dichloro-phenyl)- 532.9 phenyl)-phenyl)- [(E) stereoisomer] 125 Benzo[1,3]dioxol-5- (4-Ethoxy-phenyl)-(3-Chloro-phenyl)- 489.1 yl- [(E) stereoisomer] 357 (3,4-Dichloro-(4-Methoxy- Phenyl- phenyl)- phenyl)- [(E) stereoisomer] 358(3,4-Dichloro- (4-Methoxy- (3-Chloro-phenyl)- phenyl)- phenyl)- [(E)stereoisomer] 359 (3,4-Dichloro- (4-Methoxy- (4-Chloro-phenyl)- phenyl)-phenyl)- [(E) stereoisomer] 360 (3,4-Dichloro- (4-Methoxy-(4-Methoxy-phenyl)- phenyl)- phenyl)- [(E) stereoisomer] 361(3,4-Dichloro- (4-Methoxy- (3,4-Dichloro-phenyl)- phenyl)- phenyl)- [(E)stereoisomer] 362 (3,4-Dichloro- (4-Methoxy- (3-Methyl-phenyl)- phenyl)-phenyl)- [(E) stereoisomer] 363 (3,4-Dichloro- (4-Methoxy-(4-Methyl-phenyl)- phenyl)- phenyl)- [(E) stereoisomer] 364Benzo[1,3]dioxol-5- (4-Ethoxy-phenyl)- (3-Chloro-phenyl)- yl- [(E)stereoisomer]

The preferred compounds that follow were made according to the syntheticmethods outlined in Schemes A, B, C, D and J and as described inExamples 76, 139, 133, 134, 140, 141, 336 and 343:

-   -   3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-methyl-2-m-tolyl-propionic        acid (Example 76);    -   3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl-1H-pyrazol-3-yl]-2-fluoro-2-m-tolyl-propionic        acid (Example 139);    -   3-[5-(3,4-Dichloro-phenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazol-3-yl]-2-(3-dimethylamino-phenyl)-propionic        acid (Example 133);    -   3-[5-(3,4-Dichloro-phenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazol-3-yl]-2-quinolin-8-yl-propionic        acid (Example 134);    -   4-(15-Di-p-tolyl-1H-pyrazol-3-yl)-3-m-tolyl-butyric acid        (Example 140);    -   5-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-4-m-tolyl-pentanoic        acid (Example 141);    -   5-{2-[5-(3,4-Dichloro-phenyl)-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-1-m-tolyl-ethyl}-1H-tetrazole        (Example 336); and    -   3-[2-(4-Methoxy-phenyl)-5-p-tolyl-2H-pyrazol-3-yl]-2-naphthalen-1-yl-propionic        (Example 343).

Preferred compounds of Table 11, which are made according to thesynthetic methods outlined in Schemes A, E and F, are given by theformula:

where R² and R¹ are selected concurrently from the groups consisting of:TABLE 11 EX R² R¹ 365 Naphthalen-2-yl- Pyridin-3-yl- 366Naphthalen-2-yl- Pyridin-4-yl- 367 Naphthalen-2-yl-(6-Methyl-pyridin-2-yl)- 368 Naphthalen-2-yl- (3-Methoxy-pyridin-2-yl)-369 Naphthalen-2-yl- (5-Methoxy-pyridin-2-yl)- 370 Naphthalen-2-yl-(6-Methoxy-pyridin-3-yl)- 371 Naphthalen-2-yl- (4-Ethoxy-pyridin-2-yl)-372 Naphthalen-2-yl- (4-Dimethylamino-phenyl)- 373 Naphthalen-2-yl-(5-Dimethylamino-2-methoxy- phenyl)- 374 (3,5-Bis-dimethylamino-(4-Methyl-phenyl)- phenyl) 375 (3-Dimethylamino-4-methoxy-(4-Methyl-phenyl)- phenyl)-

Preferred compounds of Table 12, which may be made according to thesynthetic methods outlined in Schemes A, B, C, D, H and J, are given bythe formula:

where R⁵—Y— is selected from the groups consisting of: TABLE 12 EX R⁵—Y—376 (5-Oxo-4,5-dihydro-1H-[1,2,4]triazol- 3-ylsulfanyl)-methyl- 377(3H-[1,2,3]Triazol-4-ylsulfanyl)-methyl- 378(2H-[1,2,4]Triazole-3-sulfinyl)-methyl-

Preferred compounds of Table 13, which may be made according to thesynthetic methods outlined in Scheme H, are given by the formula:

where R² and R¹ of such (Z) stereoisomeric compounds are selectedconcurrently from the groups consisting of: TABLE 13 EX R² R¹ 379(4-Dimethylamino-phenyl)- (4-Dimethylamino-phenyl)- 380(4-Dimethylamino-phenyl)- Naphthalen-2-yl- 381 (4-Dimethylamino-phenyl)-(4-chloro-phenyl)- 382 (4-Dimethylamino-phenyl)- Phenyl- 383(4-Dimethylamino-phenyl)- Benzo[1,3]dioxol-5-yl- 384 Naphthalen-2-yl-(4-Dimethylamino-phenyl)- 385 Naphthalen-2-yl- Naphthalen-2-yl- 386Naphthalen-2-yl- (4-Chloro-phenyl)- 387 Naphthalen-2-yl- Phenyl- 388Naphthalen-2-yl- Benzol[1,3]dioxol-5-yl- 389 (4-Chloro-phenyl)-(4-Dimethylamino-phenyl)- 390 (4-Chloro-phenyl)- Naphthalen-2-yl- 391(4-Chloro-phenyl)- (4-chloro-phenyl)- 392 (4-Chloro-phenyl)- Phenyl- 393(4-Chloro-phenyl)- Benzo[1,3]dioxol-5-yl- 394 Phenyl-(4-Dimethylamino-phenyl)- 395 Phenyl- Naphthalen-2-yl- 396 Phenyl-(4-chloro-phenyl)- 397 Phenyl- Phenyl 398 Phenyl- Benzo[1,3]dioxol-5-yl-399 Benzo[1,3]dioxol-5-yl- (4-Dimethylamino-phenyl)- 400Benzo[1,3]dioxol-5-yl- Naphthalen-2-yl- 401 Benzo[1,3]dioxol-5-yl-(4-Chloro-phenyl)- 402 Benzo[1,3]dioxol-5-yl- Phenyl- 403Benzo[1,3]dioxol-5-yl- Benzo[1,3]dioxol-5-yl-

The preferred compounds that follow are made according to Scheme A andas described in Method 2:

-   -   2-Benzofuran-3-yl-3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-propionic        acid; and    -   2-Benzofuran-3-yl-3-[5-(4-chloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-propionic        acid.

The compounds as described above may be made according to processeswithin the skill of the art and/or which are described in the schemesand examples that follow. To obtain the various compounds herein,starting materials may be employed which carry the ultimately desiredsubstituents though the reaction scheme with or without protection asappropriate. Starting materials maybe obtained from commercial sourcesor synthesized by methods known to one skilled in the art.Alternatively, it may be necessary to employ, in the place of theultimately desired substituent, a suitable group, which may be carriedthrough the reaction scheme and replaced as appropriate with the desiredsubstituent. In the Schemes, the pyrazole is depicted with broken linesindicating that the conventional position of the unsaturation isdependent upon the position of the R¹ substituent. Any productcontaining a chiral center may be separated into its enantiomers by HPLCusing a chiral stationary phase.

Referring to Scheme A, there are disclosed the following notes andadditions. A1 is preferably isolated as an enol salt. In addition to thelithium, the sodium and potassium salts may also be used. A2 is formedas a mixture of regioisomers with either the 1,5- or 1,3-isomerpredominating. A2 regioisomers may be separated and carried forwardindividually. The reduction to A4 may be effected with a number ofreducing agents including DIBAL-H and LiAIH₄. The conversion of alcoholA4 to bromide, iodide or mesylate A7 may be carried out with variousagents including PBr₃, CBr₄/PPh₃, I₂/imidazole, or MsCl/TEA. The enolatealkylation to A8 may be carried out with R⁴ as hydrogen or alkyl. WhenR⁴ is hydrogen in A8, R⁴ as alkyl or halogen may be obtained in A9 byenolate alkylation or electrophilic fluorination. Various startingmaterials A10 may be purchased or certain such starting materials may besynthesized by homologation of aryl aIdehydes using chemistry describedby Wang (Synthetic Communications 29, (1999), 2321), or Mikolajczyk (J.Am. Chem. Soc. 120, (1998) 11633.

Referring to Scheme B, there are disclosed the following notes andadditions. The reduction to B₁ may be effected with a number of reducingagents including DIBAL-H and LiAIH₄. Displacement of the hydroxy to formbromide B2 can be carried out using a variety of reagents includingPBr₃, or CBr₄/PPh₃. Hydrolysis of the nitrile B3 to the ester B4 can becarried out with a variety of acids including HCl, TsOH, or H₂SO₄.Hydrolysis of the ester B4 to the acid B5 can be performed under basicconditions generally using LiOH. As with the reduction of ester A8 toB1, ester B4 may be reduced to a n+1 analogue of B1, which will produceaccording to the teachings in Scheme B, a n=2 analogue of B5. Thus,according to Scheme B, both a n=1 and n=2 acid B5 is produced.

Referring to Scheme C, there are disclosed the following notes andadditions. Oxidation of B1 to C1 can be performed using procedures suchas the Dess-Martin or Swern oxidations. Hydrogenation to form C3 can bedone with a variety of catalytic hydrogenation conditions such as RaneyNickel, Pd/C, CoCl₂/NaBH₄, RhCl(PPh₃)₃. Hydrolysis of ester C3 isgenerally done under basic conditions with LiOH, but other bases couldbe used.

Referring to Scheme D, there are disclosed the following notes andadditions. As shown, any of the acids, A9, B5, J4, or C4 can be employedas a starting material. Formation of amide D2 can be performed using avariety of amide bond forming conditions (see: Synthesis, (1974) 549).Dehydration with TFAA followed by cyclization of the cyano with NaN₃gave the desired tetrazole D4. Additionally D5 can be synthesized byaddition of bromide A7 to the anion of nitrile D7. Compound D5 can thenbe converted to the tetrazole D4 using NaN₃. Alternatively the specificamide D2 can be converted to the protected tetrazole D6 using TMSN₃under Mitsunobu conditions, deprotection with DBU then provides D4.

Referring to Scheme E, there are disclosed the following notes andadditions. In the manufacture of starting material E1, an aryl aceticacid ester such as A10 is condensed with appropriate terminal olefinicalkyl halide followed by Wacker oxidation to give the ester E7.Hydrolysis of the ester will give the methyl ketone E1. Coupling of acidE1 is to Kenner's safety-catch resin can be accomplished with a varietyof peptide coupling reagent including CDl, PyBOP, HOBt. Condensationwith E5 gives E3, which is then cyclized with the appropriate hydrazineto give the desired pyrazole E4 as a mixture of regioisomers. Activationof the resin with TMSCH₂N₂ followed by cleavage with hydroxide givesacids A9 as a mixture of regioisomers, which can be separated by HPLC.Alternatively, the activated sulfonamide resin can be cleaved with aminenucleophiles to provide amides A11. Scheme E follows a process similarto that disclosed in Organic Letters, Vol. 2, 2000, pages 2789 to 2792.

Referring to Scheme F, there are disclosed the following notes andadditions. Compounds of type A9 and A11 can be synthesized in a mannersimilar to scheme E, this approach is outlined in scheme F. In this casea sulfonamide linker is coupled to E1 prior to attachment to resin, tofacilitate quantitation of resin loading. Acid F2 is then coupled tomacroporous aminomethyl polystyrene support to provide F3, which issimilar to E2. Scheme F proceeds from F3 to A9 or A11 in an analogousfashion to Scheme E. Use of macroporous resin provides higher yields ofproduct and easier handling of reactions than the resin used in schemeE.

Referring to Scheme G, there are disclosed the following notes andadditions. Using the appropriate chiral auxiliary attached to theAr-acetic acid derivative G1, enolate alkylation by pyrrole A7 affordsthe desired stereochemistry about the new stereocenter in G2. Inaddition, other chiral auxiliaries such as the valine and phenylalaninederived oxazolidinones of Evans can also be used. Alternatively, theopposite enantiomer of the chiral auxiliary depicted can be used tosynthesize the opposite absolute stereochemistry of G3. As depicted, G3is the (S) configuration when R⁴ is H and the depicted chiral auxiliaryis used. For R⁴ other than H and for other chiral auxiliaries, theabsolute configuration G3 may be either the one shown or the oppositeconfiguration depending upon the conditions used.

Referring to Scheme H, there are disclosed the following notes andadditions. Oxidation of the alcohol A4 can be performed usingDess-Martin or Swern oxidation conditions to provide aldehyde H1. H1 canbe condensed with an Ar-acetic acid ester using standard aldolcondensation conditions to give the olefin-ester as a mixture of the E-and Z-isomers, which upon hydrolysis affords acids H2 (E) and H2 (2).The E- and Z-isomers maybe separated by chromatography. Alternativelythe acid H2 (E) can be obtained directly via a Perkin condensation usingan arylacetic acid and Ac₂O. In this case, only acid H2 (E) is formed.Furthermore, photoisomerization of the isolated E- or Z-isomer resultsin the creation of a mixture of E- and Z-isomers. Additionally reductionof the olefin with TsNHNH₂, or other reducing agent can provide thesaturated analogs H3.

Referring to Scheme I, there are disclosed the following notes andadditions. The alkyl bromide B2 can be displaced with several thiollinked heterocycles to give compounds such as 12 or 13. Additionally,the sulfur can be selectively oxidized to the sulfinyl compounds with anoxidant such as mCPBA to afford 14 and 15. Additionally these compoundscan be further oxidized to the sulfonyl linked heterocycles by oxidationwith such agents as H₂O₂. To obtain analogues of 12 through 17 in whichn=2, an n+1 bromide B2 may be used as the starting material. The n+1bromide B2 may be obtained as described in the paragraph followingScheme B.

Referring to Scheme J, there are disclosed the following notes andadditions. Succinic anhydride can be reacted with the enolate of amethyl ketone to provide enolates of type J1. Additions of hydrazinesprovide pyrazoles J2 as a mixture of 1,3- and 1,5 regioisomers, theseisomers can be readily separated by standard chromatographic methods.Esterification can be performed with a variety of alkyl groups to formesters J3, the preferred Alkyl group being t-Butyl. Coupling of an arylbromide with the enolate of J3 using the conditions described byBuchwald (J. Am. Chem. Soc. 123, (2001) 7996) then provide the ester ofJ4, which can be hydrolyzed to J4.

Referring to Scheme K, there are disclosed the following notes andadditions. Bromomaleic anhydride can be coupled with aryl boronic acidsusing Suzuki coupling conditions to provide compounds of type K2.Addition of the enolate of a methyl ketone affords enolates of type K2,which can then be treated with a hydrazine to afford a mixture of 1,3-and 1,5-substituted pyrazoles H2 with exclusively to (Z) olefin geometryshown. These pyrazole regioisomers can be readily separated bychromatography. Pyrazoles H2 may be converted to amides K4 throughpeptide coupling. Pyrazole H2 may be esterified to produce an alkeneequivalent compound A8, which can be used, as disclosed in Scheme B, toproduce the n=1 and n=2 analogues.

Referring to Scheme L, there are disclosed the following notes andadditions. Arylacetic acid esters can be alkylated with propargylbromides of type L1 to form alkynes of type L2. If the alkyl group is achiral auxiliary such as depicted in scheme G this transformation can beperformed to produce enatiomerically pure compounds of type L2.Friedel-Crafts type coupling of the alkyne L2 with and acid chloridethen provides alkynyl ketone L3. Addition of a hydrazine followed byhydrolysis of the ester provides pyrazoles of type L4 as a mixture of1,3- and 1,5-regioisomers. In addition if the esters L5 contain ahalogen on any of the aromatic rings (chemistry is specificallyindicated for R² in the scheme) the compound can be coupled with anamine or amide using either the copper or palladium coupling conditionsdescribed by Buchwald (J. Am. Chem. Soc. 123, (2001) 7727; J. Org. Chem.65, (2000) 1158) to obtain nitrogen substituted compounds L4 uponhydrolysis. Additionally if any of the aromatic rings in L4 are apyridine they can be oxidized to the N-oxide using mCPBA. The racemicmixtures of compounds L4 and L5 can optionally be separated into theirindividual pure enantiomers through chiral chromatography.

Referring to Scheme M, there are disclosed the following notes andadditions. Pyrazole esters of type A2 of either regioisomeric form canbe condensed with the enolate of a phenylacetic acid ester to formketoester M1. Reduction of M1 to the alcohol followed by elimination ofthe β-hydroxy ester in the presence of base results in the ester of H2,which can then be hydrolyzed to form acid H2 as a mixture of (E) and (Z)isomers. These isomers can be separated by chromatographic methods.Alternatively the ketone M1 can be protected as the ketal, and the esterhydrolyzed to form M4. Amide coupling and tetrazole formation can thenbe performed using the procedures outlined in scheme D to provide M6.Deprotection, reduction, and elimination as previously described thenafford olefinic tetrazoles of the type M7.

In addition to the teachings provided by foregoing Schemes, there aredisclosed the following notes and additions regarding the makingcompounds of formula (I) by processes that are stereoselective and/orregioselective.

It is understood that the teachings provided by foregoing Schemes arenot meant to be mutually exclusive with the teachings provided by thefollowing Schemes in their application to chemically meaningfulcombinations of process steps.

Furthermore, scheme labeling is provided herein only for the convenienceof scheme designation, but it is not meant to imply any limitation tothe schemes themselves. In addition, scheme labeling provided herein isnot meant to imply any limitation to and/or exclusion of any chemicallymeaningful combination made in light of the ordinary skill in the art,and/or in light of the present disclosure, of the teachings in one orseveral of the schemes provided herein.

Terms such as “stereoselective”, “stereoselectivity”, and morphologicvariations thereof refer to the production of stereoisomeric products inunequal amounts. As conventionally used, enantiomeric excess (oftenabbreviated as “ee”) means herein |F₍₊₎—F⁽⁻⁾|, where F₍₊₎ denotes molefraction (or mass fraction) of enantiomer (+), F⁽⁻⁾ denotes molefraction (or mass fraction) of enantiomer (−), and F₍₊₎+F⁽⁻⁾=1. Whengiven as a percentage, enantiomeric excess is 100·|F₍₊₎−F⁽⁻⁾|. Termssuch as “enantiomerically pure”, “optically pure”, and morphologicvariations thereof refer to products that satisfy ee >99%.

Terms such as “racemic”, “racemate”, and morphologic variations thereofapply as used herein to mixtures in which the enantiomers are present inequimolar amounts (ee=0) and such mixtures do not exhibit opticalactivity.

Terms such as “regioselectivity”, “regioselective”, and morphologicvariations thereof refer to the existence of a preferential direction ofbond making or breaking over other possible directions. Regioselectivityextent is given in terms of a percentage (which is also referred to asregioisomeric excess) of a desired product with certain bonding patternthat is formed in excess of other product or products with some otherbonding pattern.

Embodiments of processes illustrated herein include, when chemicallymeaningful, one or more steps such as hydrolysis, halogenation,protection, and deprotection. These steps can be implemented in light ofthe teachings provided herein and the ordinary skill in the art.

Embodiments of this invention provide compounds with a desired bondingpattern and/or with a desired chirality by processes that have a smallnumber of synthetic steps. Such small number of steps makes embodimentsof this invention particularly suitable for synthetic processes wheresignificant quantities of the desired compound are to be obtained.Scale-up processes are examples of such embodiments.

According to embodiments of this invention, compounds with a desiredchirality are synthesized with no need to resort to columnchromatographic separation. Furthermore, the compounds with a desiredchirality are synthesized in embodiments of this invention with no needto resort to process steps that involve expensive chiral auxiliarycompounds.

Referring to Scheme P, there are disclosed the following notes andadditions. Stereoselectivity is introduced through an acetylenic ketone,such as P5, obtained from a coupling of chiral acetylenic additionproduct P3 and an acid halide P4. Product P3 is obtained by astereoselective addition of a chiral ester, such as P1, with anacetylenic acid halide, such as P2. Substituent HAL in P2 and P4 is anappropriate leaving group.

The addition reaction with a chiral ester and an acetylenic acid halidewas developed in the context of this invention. It was found in thecontext of this invention that compounds P3 can be produced by thisreaction with high enantiomeric excess regarding the stereogeniccenter-shown in Scheme P with an asterisk. This enantiomeric excess wasin embodiments of this invention at least 80%. Referring todiastereomeric excess (de), embodiments of this invention yield P3 witha high diastereomeric excess. Embodiments of this invention produced P3with de of at least about 80%. Diastereomeric excess with respect to thechirality of a stereogenic center for any pair of diaestereomers isdefined analogously as enantiomeric excess is defined above.

The chiral ester was added to a cooled medium. The medium was obtainedby mixing an organic base with an acid halide in an organic solvent.Acid chlorides are examples of such acid halides, tertiary amines areexamples of such bases, and low polarity solvents are examples of suchsolvents. Trialkyl amines are preferred tertiary amines, anddimethylethyl amine is a more preferred embodiment. Other amines such astriethyl amine, diethylmethyl amine, and mixtures thereof can be used inembodiments of this invention, preferably tertiary amines whosemolecular volume is comparable to that of dimethylethyl amine. Anestimate of molecular volumes for such comparison can be performed byresorting to consultation of standard tables of atomic and molecularparameters, including radii, bond lengths, volumes, and molecularproperties that lead to an indirect estimate of molecular volumes.

Toluene is a preferred organic solvent. Other solvents such as hexaneand mixtures thereof can be used in embodiments of this invention.Preferred solvents are those that are not significantly more polar thantoluene, so that the solvent medium preferably has a dielectric constantnot greater than about 6, and more preferably not greater than about 3.Organic solvents whose dielectric constant is not greater than about 6are referred herein as “low polarity organic solvents”. The cooledmedium is preferably at a temperature in the range from about −70° C. toabout −85° C.

Compound P2 is more preferably an acid halide, in which case thesubstituent HAL is a halo group, more preferably Cl or Br, and mostpreferably Cl. Substituent Ar is defined above. Substituent DER isdetermined by the choice of ester P1. In some embodiments of thisinvention, ester P1 is ethyl lactate, in which case -DER is

where “o-” denotes the attachment member. In general, -DER is —O-DER′where DER′ is the moiety of the chiral ester that attaches through the Omember to form a compound P3.

Compound P2 is either available or it can be prepared by an acid halideformation reaction. In embodiments of this invention in which HAL is Cl,and Ar is m-tolyl, compound P2 was obtained from 2-m-tolyl-pent-4-ynoicacid and oxalyl chloride under suitable acid chloride formationconditions.

The acid that is used in the formation of the acetylenic compound fromwhich an acetylenic acid halide is subsequently formed is eitheravailable or it can be obtained by an alkylation reaction. In someembodiments, 2-m-tolyl-pent-4-ynoic acid was obtained by alkylatingm-tolyl acetic acid with propargyl bromide under suitable alkylationconditions.

The alkylation and acid halide formation steps are not displayed inScheme P for brevity, but they can be implemented in light of theteachings provided herein. Starting reagents for the alkylation and acidhalide formation reactions are readily available or can be preparedaccording to methodology within the ordinary skill in the art.

An asterisk (*) next to a C center in the schemes provided hereindenotes a single stereogenic center. The chirality of the stereogeniccenter of compound P3 is determined by the chirality in chiral ester P1.In some embodiments, P1 was chosen to be (S)-(−)-ethyl lactate, so thateach stereogenic center denoted by an asterisk in scheme P was in suchcase an S-center. Accordingly, the local stereospecific environment ofthe center

in Scheme P was the S-center

in such embodiments. This choice is illustrative, and another electionis possible. For example, the stereogenic center can be R, in which casea chiral ester with R chirality is suitably chosen. A desired chiralitycan also be introduced by using a hydroxy ester, such as anα-hydroxycarboxylic ester

When such α-hydroxycarboxylic ester is used, DER is

and DER′ is

that the α-hydroxycarboxylic ester is DER′-OH. R^(v) and R^(v,) aregroups such that compound P7 can be hydrolyzed to P8. R^(v) and R^(v,)are independently chosen preferably from the group of linear andbranched C₁₋₄alkyl.

In some embodiments, compound P3 is a chiral 2-arylpentynoic acidderivative. An example of such P3 is 2-m-tolyl-pent-4-ynoic acid1-ethoxycarbonyl-ethyl ester.

Chiral acetylenic ketone P5 is obtained by coupling suitably substitutedacid halide P4 with the addition product P3. HAL in compound P4 isdefined as with respect to P2. This coupling is performed in someembodiments of this invention by a Sonogashira reaction.

Sonogashira reaction conditions include the presence of apalladium-containing catalyst, such as palladium on carbon,Pd(PPh₃)₂Cl₂, Pd₂(dba)₃, Pd₂(dba)₃*CHCl₃, Pd(P^(t)Bu₃)₂,Pd₂(dba)₃·CHCl₃/Pd(P^(t)Bu₃)₂, Pd(OAc)₂, Pd(PhCN)₂Cl₂, and PdCl₂, and abase, such as N-methylmorpholine (NMM), triethyl amine,1,4-dimethylpiperazine, diisopropylethyl amine, and mixtures thereof ina solvent such as THF, DME, dioxane, DCE, DCM, toluene, acetonitrile,and mixtures thereof at a temperature from 0° C. to 100° C. Preferredbases are not significantly stronger than NMM and they are compatiblewith the presence of Cu(I) species in the medium.

A copper compound is used as a catalyst in this reaction, such as Cu(I)compound. Such Cu(I) catalyst is preferably incorporated in the reactionmedium as substoichiometric quantities of a copper salt, such as CuI orCuBrMe₂S. The use of phosphine ligands, such as PPh₃ or P(^(t)Bu)₃, ispart of the methodology of some embodiments of the present invention.

As in other process steps in the context of embodiments of thisinvention, the use of a high polarity solvent may increase the rate andreduce by-product formation in these reactions. Such high polaritysolvent is provided in some embodiments as a mixture of a first solventwith a cosolvent that increases the dielectric constant of the mixturewith respect to the dielectric constant of such first solvent. Forexample, one of ordinary skill in the art will recognize in light ofthis disclosure that the use of water as such cosolvent may increase therate and reduce by-product formation in these reactions.

In a preferred embodiment, the palladium source isPd₂(dba)₃·CHCl₃/Pd(P′Bu₃)₂, Pd(PPh₃)₂Cl₂, or palladium on carbon, thebase is NMM, the solvent is THF, toluene, THF with toluene, or a mixtureof 1,2-dimethoxyethane (DME) and water, and the temperature is betweenroom temperature and 80° C. In a particularly preferred embodiment, thepalladium source is Pd(PPh₃)₂Cl₂, the base is NMM, the solvent is THFwith toluene, a catalytic quantity of CuI or CuBrMe₂S is used, and thereaction temperature is room temperature to reflux temperature, mostpreferably room temperature.

R² and HAL are defined above. In some embodiments, compound P5 is6-(3,4-dichloro-phenyl)-6-oxo2-m-tolyl-hex-4-ynoic acid1-ethoxycarbonyl-ethyl ester.

Regioselectivity with respect to the pyrazole framework in P7 isachieved by a condensation reaction involving compound P5 and a suitablysubstituted hydrazine P6. In some embodiments P6 is a suitablysubstituted hydrazine in other than free base form, referred to hereinas non-free base form, in which the hydrazine is in the presence of anacid, thus forming the combinations that these two components form whenthey are present in the same medium. An example of such embodiments is asuitably substituted hydrazine hydrochloride. In other embodiments, P6is a suitably substituted hydrazine in free base form. P6 is preferablya suitably substituted hydrazine in non-free base form in embodiments ofthe process shown in Scheme P. Substituent R¹ in P6 is defined above,and it is chosen according to the type of substitution desired inproduct P8.

Compound P7 is a pyrazole derivative wherein n=1 and R³ is H. Otherembodiments of this pyrazole derivative, and also of P8 and otherpyrazole derivatives referred to herein, such as Q3, Q8, R5.1, R5-R8,and S8 in the following Schemes, can have other assignments of n and R³in light of the definitions of n and R³ given above, and they can beprepared according to teachings given herein, such as the teachingsprovided in the context of Scheme A.

The term “substituted” as applied to the hydrazines referred to incondensations described herein is to be read in light of the genericform of compounds P6, where R¹ is defined herein, and it can be, interalia, H. Therefore, “substituted hydrazine” in this context includes“substituted” (wherein R¹ is a substituent other than H) and“unsubstituted” (wherein R¹ is H) hydrazine as exemplified by P6together with the definition of R¹ given herein.

The regioselective condensation reaction with an acetylenic ketone and asuitably substituted hydrazine to produce a preferred bonding pattern incompound P7 was developed in the context of this invention. It was foundthat compounds with a nitrogen substitution pattern in the pyrazoleframework as shown in P7 in the surrounding chemical environment ofcompounds of this invention can be produced by this reaction with highregioselectivity, which reached in embodiments of this invention atleast about 80%, or a molar ratio of 1:4, with the isomer in excessbeing the isomer with the pyrazole framework substituted as shown inScheme P.

An inorganic base and a suitably substituted hydrazine were added inembodiments of this invention to a solution of acetylenic ketone P5 andlater quenched with an acidic solution to obtain a medium with an acidicpH.

Examples of acidic solutions are aqueous acidic solutions, such thattheir acidity is suitable to bring the medium pH to a sufficiently lowpH value. Quenching to an acidic pH was performed in some embodimentswith HCl_((aq)) until the medium pH was in the range from about 2 toabout 3. The hydrazine in embodiments of this invention is preferablyincorporated as a hydrochloride, and one example of suitably substitutedhydrazines used in the context of this invention is 4-methoxyphenylhydrazine.HCl.

Compound P7 in Scheme P shows a pyrazole framework

with one of the nitrogen members in the pyrazole framework substituted.This substitution is illustrated in P7 by substituent R¹. It isunderstood that the other regioisomer is also produced in the same stepof formation of P7; and that such other regioisomer has substituent R¹in the nitrogen member of the pyrazole framework that is shownunsubstituted in Scheme P, whereas the substituted nitrogen member inthe same framework is unsubstituted in such other regioisomer.

The solvent in the solution of P5 is preferably an organic solvent, suchas benzene, DCM, DCE, THF, DMF, acetonitrile, hexamethylphosphoramide(HMPA), hexane, pentane, alcohol, and mixtures thereof. Regioselectivityfor the nitrogen substitution pattern in the pyrazole framework shown inScheme P (1-(R¹)-1H-pyrazol substitution) was achieved in embodiments ofthis invention with a non-protic solvent (a solvent that does notreadily release a proton), such as THF, TMF, and combinations thereof,preferably THF. Other illustrative non-protic solvents include ether,toluene, and dichloromethane. The other nitrogen substitution pattern,2-(R¹)-2H-pyrazol, was preferentially obtained with a protic solvent (asolvent that more readily releases a proton), such as a carboxylic acid,water, an alcohol and alcohol mixtures, mixtures thereof, and preferablymethanol, ethanol, and mixtures thereof.

Examples of inorganic bases that can be used in this condensation arealkali metal hydroxides, such as KOH, NaOH, and mixtures thereof, andalkali metal carbonates, such as Na₂CO₃, K₂CO₃, Cs₂CO₃, and mixturesthereof. Other bases that would perform in this reaction medium as thebases exemplified herein can also be used. A carbonate is preferred,such as Cs₂CO₃.

Embodiments of this invention achieved regioselectivity referred to thenitrogen substitution in the pyrazole framework of at least 1:4, whereinthe more abundant isomer conforms to the nitrogen substitution patternexhibited by compound P7 where the condensation is performed undersuitable conditions described herein. In some embodiments, P5 was6-(3,4-dichloro-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acid1-ethoxycarbonyl-ethyl ester, and P6 was 4-methoxyphenyl hydrazine.HCl,in which case P7 was embodied by3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid 1-ethoxycarbonyl-ethyl ester. A smaller amount of isomer345-(3,4-dichloro-phenyl)-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-2-m-tolyl-propionicacid 1-ethoxycarbonyl-ethyl ester (P7′) was also formed (nitrogensubstitution pattern “2-( . . . )-2H-pyrazol”, a pattern that is notshown in Scheme P), and the molar ratio of this two products was 1:4referred to relative amounts of P7′ and P7, or 20% and 80%,respectively.

Removal of substituent DER by a suitable process leads to the formationof the final product. Scheme P illustrates an embodiment of P7 whereinDER is such that P7 is an ester, such as a lactate ester. In suchembodiments, substituent DER is preferably removed by hydrolysis.Removal of DER leads to product P8. Acetic and hydrochloric acids wereused in some embodiments of this invention in the ester hydrolysis.

In some embodiments, compound P7 was3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid 1-ethoxycarbonyl-ethyl ester, in which case P8 was(S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid. This embodiment of P8 was obtained with an S-enantiomeric excessee(S) of at least about 80%, which corresponds to a molar enantiomericratio R/S of at least about 1:9.

The enantiomeric excess of a product obtained according to the presentinvention can be increased by crystallization, whether the product isobtained by a synthesis as in Scheme P or by resolution of a racemate.An enantiomeric excess of 80% may be acceptable for some applications ofcompounds P8. Embodiments of P8 that are to be eventually obtained inenantiomerically pure form are further purified by crystallization.

Embodiments of acids include herein any one of the acid forms such asthe acid itself and derivatives thereof such as salts, whether any suchsalt is isolated or in solution. For example, embodiments of P8accordingly include P8 salts.

Enantiomeric purification of compounds P8 (not displayed in Scheme P asan additional step) was developed in the context of this invention. Itwas found in the context of this invention that compounds P8 crystallizeunder suitable conditions. A salt of P8 is formed to this effect. Suchsalt is preferably an inorganic salt, such as an alkali metal salt.Other salts are amine salts.

For example an aqueous solution of an inorganic base, preferably ahydroxide, was added to a solution of P8 in an organic solvent, such asTHF. Examples of such hydroxides are sodium and potassium hydroxides,but other bases can also be used. Evaporation in a rarefied environmentof some of the mixture components is performed until a small amount ofwater is left in the medium. This residue with a small amount of wateris dissolved in a suitable solvent and subsequently crystallized out ofa suitable crystallization medium.

It was found in the context of this invention that a suitablecrystallization medium is provided by a medium with at least one solventcomponent, “first component”, and at least another component, “secondcomponent”. The first component is such that the residue is solubletherein, and the second component is such that the residue is lesssoluble than in the first component. For example the residue can beinsoluble in the second component; in other embodiments the residue isrelatively less soluble in such second component. THF is a preferredembodiment of the first component, and CH₃CN is a preferred embodimentof the second component.

In a preferred crystallization process, the residue with a small amountof water is dissolved in the first component, and then the secondcomponent is added, from which medium the P8 salt separates. The term“crystallization” is generically used herein for this process, but it isunderstood that the salt separates in some embodiments as a crystallineproduct, in other embodiments it separates as a semicrystalline product,and it can separate in other embodiments as an amorphous product.

In addition to the preferred THF—CH₃CN medium as first-second componentmedium, other illustrative first-second component media includeMeOH—CH₃CN, CH₂Cl₂-toluene, CH₂Cl₂-hexane, and CH₂Cl₂-(toluene-hexane)media, wherein “(toluene-hexane)” refers to mixtures of toluene andhexane. THF, MeOH and CH₂Cl₂ are examples of first component, and CH₃CN,toluene, hexane, and (toluene-hexane) are examples of second component.

In preferred embodiments, this amount of water left in the medium doesnot differ by more than about 20% from an equimolar amount of water withrespect to the amount of P8 salt. For example, in some embodiments thisamount of water did not exceed about 1.2 times the amount of water thatwould be equimolar to the amount of P8 salt. In other embodiments, thisamount of water was not less than about 0.8 times the amount of waterthat would be equimolar to the amount of P8 salt. In these embodiments,the amount of water left in the medium is within about 20% of the wateramount that would be equimolar with the amount of P8 salt. In morepreferred embodiments, this amount of water left in the medium does notdiffer by more than about 10% from an equimolar amount of water withrespect to the amount of P8 salt, in still more preferred embodiments,this amount of water left in the medium does not differ by more thanabout 5% from an equimolar amount of water with respect to the amount ofP8 salt, and in most preferred embodiments this amount of water left inthe medium is about equimolar with respect to the amount of P8 salt.

Crystallization in the context of this invention permits not onlyenantiomeric enrichment, but also the enrichment of a desiredregioisomer. Products with a desired enantiomeric excess and/or adesired degree of regioisomeric enrichment are obtained bycrystallization as described herein.

It was found in the context of this invention that inorganic and organicsalts are obtained by this crystallization method. Examples of inorganicsalts are sodium and potassium salts. Examples of organic salts areamine salts, such as meglumine, tromethamine, tributylamine, andethylene diamine salts.

The terms “compound (I)” in the context of this invention refer to anyof the forms of compound (I), such as the solvent free compound, asolvate thereof, including a hydrate thereof, the compound as insolution, and any crystalline, semicrystalline (semicrystallinereferring to a mixture of crystalline and amorphous material), oramorphous form thereof, and mixtures thereof. For example, the terms “asalt of P8” include any one of the forms of such salt, whetheranhydrous, or in the form of a solvate, such as any form of hydrate. Thesame illustration applies to Q8, R8, and S8. Furthermore, thecrystallization described herein also applies to the final productsobtained according to this invention, such as the final productsreferred to in Schemes Q, R, and S.

Enantiomeric excess achieved by crystallization according to thisinvention can readily reach and exceed 90%, and also enantiomericpurity. Regioisomeric enrichment achieved by crystallization accordingto this invention converts a product with about 80% (regioisomericexcess of at least 80%) of one regioisomer to a product with at least90% (regioisomeric excess of at least 90%) of the same regioisomer, andembodiments of this invention achieved a regioisomeric enrichment suchthat the crystallization product was at least 99% (regioisomeric excessof at least 99%) in one of the regioisomers.

When P8 was embodied by(S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid, purification by crystallization led to the isolation of anenantiomerically pure salt, such as (S)-sodium3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate,with embodiments of this invention reaching ee(S) >99.9%.

Embodiments of processes schematically illustrated in Scheme P comprisea 6-step synthesis (these steps referring in some embodiments toalkylation, acid halide formation, stereoselective addition,regioselective condensation, and hydrolysis) in which a chosen chiralityat a specific stereogenic center is generated at an early syntheticstage by a stereoselective addition between a chiral ester, such as P1,and an acid halide, such as P2. Chiral acetylenic ketone P3 is thusgenerated. Such embodiments also comprise regioselective condensationand recrystallization enantioenrichment to an optically pure finalproduct. A stereoselective addition in some embodiments of thisinvention was implemented by using an inexpensive chiral reagent such as(S)—(−)-ethyl lactate.

In contrast with embodiments of the present invention, syntheticprocesses that rely on other approaches, such as processes that requirecolumn chromatographic separation, comprise at least eight steps. Alsoin contrast with embodiments of the present invention, other processesrely on expensive chiral auxiliary reagents.

Some embodiments include methods of making a compound of formula (I),enantiomers, diastereomers, racemics, pharmaceutically acceptable salts,esters, and amides thereof, comprising: an addition reaction of a chiralester and an acetylenic acid halide to form a chiral acetylenic additionproduct. More specifically, additional embodiments include those methodswherein any one of the following features applies:

-   -   said chiral acetylenic addition product is produced with an        enatiomeric excess of at least about 80%;    -   said chiral acetylenic addition product is produced by mixing an        acetylenic acid halide, an organic base, and said chiral ester        in an organic solvent;    -   said acid halide is an acid chloride;    -   said organic base is a tertiary amine;    -   said organic base is a trialkyl amine;    -   said organic base is dimethylethyl amine;    -   said organic base is a tertiary amine whose molecular volume is        about the molecular volume of dimethylamine;    -   said organic solvent is a low polarity organic solvent;    -   said organic solvent is an organic solvent having a dielectric        constant and said dielectric constant is not greater than about        6;    -   said organic solvent is an organic solvent having a dielectric        constant and said dielectric constant is not greater than about        3;    -   said organic solvent is an organic solvent having a dielectric        constant and said dielectric constant is not greater than the        dielectric constant of toluene;    -   said chiral acetylenic addition product is produced by mixing an        acetylenic acid halide and an organic base to form an organic        mixture, cooling said organic mixture to a temperature in the        range from about −70° C. and −85° C., and adding said chiral        ester;    -   said chiral ester is a chiral hydroxy ester;    -   said chiral ester is an a-hydroxycarboxylic ester;    -   said chiral acetylenic addition product is a chiral        2-arylpentynoic acid derivative;    -   said chiral acetylenic addition product is        2-m-tolyl-pent-4-ynoic acid 1-ethoxycarbonyl-ethyl ester;    -   said chiral ester is ethyl lactate;    -   said acetylenic acid halide is 2-m-tolyl-pent-4-ynoyl chloride;    -   wherein the Ar attached carbon is saturated and has the        configuration    -   said R¹, optionally substituted with R^(p) as described above,        is selected from the group GR¹, said group GR¹ consisting of        hydrogen:        -   a) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-,            7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-,            7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4, 5, 6 or 7-yl,            1,2,3,4-tetrahydro-isoquinolin-4, 5, 6 or 7-yl,        -   b) 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or            7-benzothiophenyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6-            or 7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl, 4-, 5-, 6- or            7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl,            imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl,            pyrazolo[1,5-a]pyridin-4, 5, 6 or 7-yl,            1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl,            1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl,            1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl,            1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl,    -   c) 5-, 6-, 7- or 8-isoquinolinyl, 5-, 6-, 7- or 8-quinolinyl,        5-, 6-, 7- or 8-quinoxalinyl, 5-, 6-, 7- or 8-quinazolinyl,        -   d) naphthyl,        -   e) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl,            1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,            thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl,            pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-indoxazinyl,            2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or            3-benzofuranyl, 2- or 3-indolyl, 2-benzthiazolyl,            2-benzimidazolyl, 3-indazolyl,        -   f) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl,            pyridazinyl, 1-,3- or 4-isoquinolinyl, 2-, 3- or            4-quinolinyl, 2- or 3-quinoxalinyl, 2- or 4-quinazolinyl,            1-oxy-pyridin-2, 3, or 4-yl,        -   g) cyclopentyl, cyclohexyl, cycloheptyl, piperidin-2,3 or            4-yl, 2-pyrrolin-2, 3, 4 or 5-yl, 3-pyrrolin-2 or 3-yl,            2-pyrazolin-3, 4 or 5-yl, morpholin-2, 3, 5 or 6-yl,            thiomorpholin-2, 3, 5 or 6-yl, piperazin-2, 3, 5 or 6-yl,            pyrrolidin-2 or 3-yl, homopiperidinyl, adamantanyl,        -   h) methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,            t-butyl, n-pentyl, pent-2-yl, hexyl, hex-2-yl, and        -   i) —C₁₋₂alkyl mono-substituted with any one of the preferred            substituents of a) to g),            -   in more specific embodiments R¹, optionally substituted                with R^(p) as described above, is selected from the                group PGR¹, said group PGR¹ consisting of H, methyl,                phenyl, benzyl, cyclohexyl, cyclohexylmethyl, pyridinyl,                pyridinylmethyl and pyridinyl-N-oxide,            -   and specific R¹ are selected from the group SGR1, said                group SGR¹ consisting of phenyl, 2-methoxy-phenyl,                3-methoxy-phenyl, 4-methoxy-phenyl,                2,3-dimethoxy-phenyl, 3,4-dimethyoxy-phenyl,                2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl,                2,4-dicloro-phenyl, 3,4-dichlorophenyl,                2,4-dichlorophenyl, 2,5-dichlorophenyl, 2-methyl-phenyl,                3-methyl-phenyl, 4-methyl-phenyl, 2,5-dimethyl-phenyl,                2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl,                4-trifluoromethyl-phenyl, 3-trifluoromethoxy-phenyl,                4-trifluoromethoxy-phenyl, 4-t-butyl-phenyl, benzyl,                cyclohexyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,                4-triflouromethyl-2-pyridyl, 2-pyridyl-N-oxide,                4-methanesulfonyl-phenyl, 4-phenoxy-phenyl,                4-isopropyl-phenyl, 4-ethoxy-phenyl, 4-hydroxy-phenyl,                4-pyridinyl-methyl, benzo[1,3]diox-5-yl, 2,3-diydro                benzo[1,4]dioxin-6-yl and cyclohexylmethyl;    -   said R^(p) is selected from the group GR^(p), said group GR^(p)        consisting of —OH, —CH₃, —CH₂CH₃, i-propyl, t-butyl, —OCH₃,        —OCH₂CH₃, —OCH(CH₃)₂, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, —Ocyclopentyl, —Ocyclohexyl, phenyl, —Ophenyl,        benzyl, —Obenzyl, —CN, —NO₂, —C(O)NH₂, —C(O)N(CH₃)₂,        —C(O)NH(CH₃), —NH(CO)H, —NHCOCH₃, —NCH₃(CO)H, —NCH₃COCH₃,        —NHSO₂CH₃, —NCH₃SO₂CH₃, —C(O)CH₃, —SOCH₃, —SO₂CH₃, —SO₂NH₂,        —SO₂NHCH₃, —SO₂N(CH₃)₂, —SCF₃—F, —Cl, —Br, I, —CF₃, —OCF₃,        —COOH, —COOCH₃, —COOCH₂CH₃, —NH₂, —NHCH₃, —NHCH₂CH₃,        —NH(CH₂CH₂CH₃), —NH(CH(CH₃)CH₂CH₃), —NH(allyl), —NH(CH₂(CH₃)₂),        —N(CH₃)₂, —N(CH₂CH₃)₂, —NCH₃(CH₂CH₂CH₃), —NCH₃(CH₂CH₃),        —NCH₃(CH(CH₃)₂), pyrrolidin-2-one-1-yl, azetidinyl,        piperidin-1-yl, 2- or 3-pyrrolin-1-yl, morpholin-4-yl,        thiomorpholin-4-yl, piperazin-1-yl, pyrrolidin-1-yl,        homopiperidin-1-yl,        -   and in more specific embodiments R^(p) is selected from the            group PGR^(p), said group PGR^(p) consisting of hydrogen,            methyl, methoxy, ethoxy, chloro, fluoro, trifluoromethyl,            trifluoromethoxy, t-butyl, methanesulfonyl, phenoxy,            isopropyl and hydroxy;    -   said R², optionally substituted with R¹ as described above, is        selected from the group GR², said group GR² consisting of:        -   i) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-,            7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-,            7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4, 5, 6 or 7-yl,            1,2,3,4-tetrahydro-isoquinolin-4, 5, 6 25 or 7-yl,        -   ii) 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or            7-benzothiophenyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6-            or 7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl, 4-, 5-, 6- or            7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl,            imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl,            pyrazolo[1,5-a]pyridin-4, 5, 6 or 7-yl,            1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl,            1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl,            1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl,            1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl,        -   iii) 5-, 6-, 7- or 8-isoquinolinyl, 5-, 6-, 7- or            8-quinolinyl, 5-, 6-, 7- or 8-quinoxalinyl, 5-, 6-, 7- or            8-quinazolinyl,        -   iv) naphthyl,        -   v) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl,            1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,            thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl,            pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-indoxazinyl,            2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or            3-benzofuranyl, 2- or 3-indolyl, 2-benzthiazolyl,            2-benzimidazolyl, 3-indazolyl, and        -   vi) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl,            pyridazinyl, 1-, 3- or 4-isoquinolinyl, 2-, 3- or            4-quinolinyl, 2- or 3-quinoxalinyl, 2- or 4-quinazolinyl,            -   in more specific embodiments R², optionally substituted                with R^(q) as described above, is selected from the                group PGR², said group PGR² consisting of phenyl,                naphthalenyl, pyridinyl, thiophenyl, benzothiophenyl,                furanyl, benzofuranyl, indolyl, indolinyl, isoquinolinyl                and quinolinyl,            -   and specific R² are selected from the group SGR², said                group SGR² consisting of 4-methyl-phenyl,                2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl,                3,4-dichloro-phenyl, benzo[1,3]dioxol-5-yl, 2,3-diydro                benzo[1,4]dioxin-6-yl, 4-methoxy-phenyl, phenyl,                4-phenoxy-phenyl, naphthalen-2-yl, pyridin-3-yl,                2-chloro-pyridin-3-yl, pyridin-4-ylmethyl,                4-benzyloxy-phenyl, 4-dimethylamino-phenyl,                4-bromo-3-methyl-phenyl, 3-methoxy-4-methyl-phenyl,                3-cyclopentyloxy-4-methoxy-phenyl,                4-bromo-2-chloro-phenyl, 4-bromo-phenyl,                3-dimethylamino-phenyl, 4-morpholin-1-yl-phenyl,                4-pyrrolidin-1-yl-phenyl, 4-(N-propylamino)-phenyl,                4-(N-isobutylamino)-phenyl, 4-diethylamino-phenyl,                4-(N-allylamino)-phenyl, 4-(N-isopropylamino)-phenyl,                4-(N-methyl-N-propylamino)-phenyl,                4-(N-methyl-N-isopropylamino)-phenyl,                4-(N-methyl-N-ethylamino)-phenyl, 4-amino-phenyl,                4-(N-methyl-N-propylamino)-2-chloro-phenyl,                4-(N-ethyl-N-methylamino)-2-chloro-phenyl,                4-(pyrrolidin-1-yl)-2-chloro-phenyl,                4-azetidinyl-phenyl, 4-(pyrrolidin-2-one-1-yl)-phenyl,                4-bromo-3-methyl-phenyl, 4-chloro-3-methyl-phenyl,                1-methyl-5-indolinyl, 5-indolinyl, 5-isoquinolinyl,                6-quinolinyl, benzo[1,3]diox-5-yl and                7-methoxy-benzofuran-2-yl;    -   said R^(q) is selected from the group GR^(q), said group GR^(q)        consisting of —OH, —CH₃, —CH₂CH₃, i-propyl, t-butyl, —OCH₃,        —OCH₂CH₃, —OCH(CH₃)₂, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, —Ocyclopentyl, —Ocyclohexyl, phenyl, —Ophenyl,        benzyl, —Obenzyl, —CN, —NO₂, —C(O)NH₂, —C(O)N(CH₃)₂,        —C(O)NH(CH₃), —NH(CO)H, —NHCOCH₃, —NCH₃(CO)H, —NCH₃COCH₃,        —NHSO₂CH₃, —NCH₃SO₂CH₃, —C(O)CH₃, —SOCH₃, —SO₂CH₃, —SO₂NH₂,        —SO₂NHCH₃, —SO₂N(CH₃)₂, —SCF₃—F, —Cl, —Br, I, —CF₃, —OCF₃,        —COOH, —COOCH₃, —COOCH₂CH₃, —NH₂, —NHCH₃, —NHCH₂CH₃,        —NH(CH₂CH₂CH₃), —NH(CH(CH₃)CH₂CH₃), —NH(allyl), —NH(CH₂(CH₃)₂),        —N(CH₃)₂, —N(CH₂CH₃)₂, —NCH₃(CH₂CH₂CH₃), —NCH₃(CH₂CH₃),        —NCH₃(CH(CH₃)₂), pyrrolidin-2-one-1-yl, azetidinyl,        piperidin-1-yl, 2- or 3-pyrrolin-1-yl, morpholin-4-yl,        thiomorpholin-4-yl, piperazin-1-yl, pyrrolidin-1-yl,        homopiperidin-1-yl;        -   and in more specific embodiments R^(q) is selected from the            group PGR^(q) said group PGR¹ consisting of methyl, bromo,            chloro, methoxy, cyclopentyloxy, phenoxy, benzyloxy,            pyrrolidinyl, N-methyl-N-ethylamino and dimethylamino;    -   there are 0, 1 or 2 R^(q) substituents;    -   said R³ is selected from the group consisting of —H, —F, Cl, Br        and —CH₃, most preferably R³ is H;    -   said n is 0, or 1.    -   said R⁴ is selected from the group consisting of —H, —F and        —CH₃, most preferably R⁴ is H;    -   said Ar, optionally substituted with R^(r) as described above,        is selected from the group GA^(r), said group GA^(r) consisting        of:        -   A) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-,            7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-,            7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4, 5, 6 or 7-yl,            1,2,3,4-tetrahydro-isoquinolin-4, 5, 6 or 7-yl,        -   B) 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or            7-benzothiophenyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6-            or 7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl, 4-, 5-, 6- or            7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl,            imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl,            pyrazolo[1,5-a]pyridin-4, 5, 6 or 7-yl,            1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl,            1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl,            1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl,            1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl,        -   C) 5-, 6-, 7- or 8-isoquinolinyl, 5-, 6-, 7- or            8-quinolinyl, 5-, 6-, 7- or 8-quinoxalinyl, 5-, 6-, 7- or            8-quinazolinyl,        -   D) naphthyl,        -   E) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl,            1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,            thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl,            pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-indoxazinyl,            2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or            3-benzofuranyl, 2- or 3-indolyl, 2-benzthiazolyl,            2-benzimidazolyl, 3-indazolyl, and        -   F) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl,            pyridazinyl, 1-, 3- or 4-isoquinolinyl, 2-, 3- or            4-quinolinyl, 2- or 3-quinoxalinyl, 2- or 4-quinazolinyl,            -   and in more specific embodiments Ar, optionally                substituted with R^(r) as described above, is selected                from the group PGAr, said group PGA rconsisting of                phenyl, naphthalenyl, benzofuran-3-yl, 4, 5, 6 or                7-benzothiophenyl, 4, 5, 6 or 7-benzo[1,3]dioxolyl,                8-quinolinyl, 2-indolyl, 3-indolyl and pyridinyl,            -   and specific Ar are selected from the group SGAr, said                group SGAr consisting of phenyl, 2-methyl-phenyl,                3-methyl-phenyl, 4-rethyl-phenyl, 2,5-dimethyl-phenyl,                2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl,                2-fluoro-3-trifluoromethyl-phenyl, 2-fluoro-phenyl,                2,3-difluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl,                4-chloro-phenyl, 2,3-dicloro-phenyl, 3,4-dichlorophenyl,                2,6-dichlorophenyl, 3-iodo-phenyl,                2-chloro-4-fluoro-phenyl, benzofuran-3-yl,                2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl,                2,3-dimethoxy-phenyl, 3-trifluoromethoxy-phenyl,                4-trifluoromethoxy-phenyl, 3-ethoxy-phenyl,                3-trifluoromethylsulfanyl-phenyl, naphthalen-1-yl,                naphthalen-2-yl, benzo[b]thiophen-4-yl, 3-nitro-phenyl,                benzo[1,3]dioxol-5-yl, pyridin-3-yl and pyridin-4-yl,                3-indolyl, 1-methyl-indol-3-yl, 4-biphenyl,                3,5-dimethyl-phenyl, 3-isopropoxy-phenyl,                3-dimethylamino-phenyl, 2-flouro-5-methyl-phenyl,                2-methyl-3-triflouromethyl-phenyl;    -   there are 0, 1 or 2 R^(r) substituents;    -   wherein R^(r) is selected from the group GR^(r), said group        GR^(r) consisting of —OH, —CH₃, —CH₂CH₃, -propyl, -t-butyl,        —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, —Ocyclopentyl, —Ocyclohexyl, phenyl,        —Ophenyl, benzyl, —Obenzyl, —CN, —NO₂, —C(O)NH₂, —C(O)N(CH₃)₂,        —C(O)NH(CH₃), —NH(CO)H, —NHCOCH₃, —NCH₃(CO)H, —NCH₃COCH₃,        —NHSO₂CH₃, —NCH₃SO₂CH₃, —C(O)CH₃, —SOCH₃, —SO₂CH₃, —SO₂NH₂,        —SO₂NHCH₃, —SO₂N(CH₃)₂, —SCF₃, —F, —Cl, —Br, I, —CF₃, —OCF₃,        —COOH, —COOCH₃, —COOCH₂CH₃, —NH₂, —NHCH₃, —NHCH₂CH₃,        —NH(CH₂CH₂CH₃), —NH(CH(CH₃)CH₂CH₃), —NH(allyl), —NH(CH₂(CH₃)₂),        —N(CH₃)₂, —N(CH₂CH₃)₂, —NCH₃(CH₂CH₂CH₃), —NCH₃(CH₂CH₃),        —NCH₃(CH(CH₃)₂), pyrrolin-2-one-1-yl, azetidinyl,        piperidin-1-yl, 2- or 3-pyrrolin-1-yl, morpholin-4-yl,        thiomorpholin-4-yl, piperazin-1-yl, pyrrolidin-1-yl,        homopiperidin-1-yl;        -   and in more specific embodiments said R^(r) is selected from            the group PGR^(r), said group PGR^(r) consisting of methyl,            methoxy, ethoxy, isopropoxy, dimethylamino, fluoro, chloro,            iodo, trifluoromethyl, trifluoromethoxy, nitro, phenyl and            trifluoromethylsulfanyl;    -   said R⁵ is selected from the group GR⁵, said group GR⁵        consisting of:        -   I) —COOH, —COOCH₃, —COOCH₂CH₃,        -   II) —CONH(CH₃), —CONH(CH₂CH₃), —CONH(CH₂CH₂CH₃),            —CONH(CH(CH₃)₂), —CONH(CH₂CH₂CH₂CH₃), —CONH(CH(CH₃)CH₂CH₃),            —CONH(C(CH₃)₃), —CONH(cyclohexyl),            —CONH(2-hydroxy-cyclohexyl), —CON(CH₃)₂, —CONCH₃(CH₂CH₃),            —CONCH₃(CH₂CH₂CH₃), —CONCH₃(CH(CH₃)₂),            —CONCH₃(CH₂CH₂CH₂CH₃), —CONCH₃(CH(CH₃)CH₂CH₃),            —CONCH₃(C(CH₃)₃), —CON(CH₂CH₃)₂, —CO-piperidin-1-yl,            —CO-morpholin-4-yl, —CO-piperazin-1-yl,            —CO-imidazolidin-1-yl, —CO-pyrrolidin-1-yl,            —CO-2-pyrrolin-1-yl, —CO-3-pyrrolin-1-yl,            —CO-2-imidazolin-1-yl, —CO-piperidin-1-yl, and        -   III) -tetrazolyl, 1H-[1,2,4]triazol-5-ylsulfinyl,            1H-[1,2,4]triazol-5-ylsulfonyl,            1H-[1,2,4]triazol-5-ylsulfanyl,            -   and in more specific embodiments R⁵ is selected from the                group PGR⁵, said group PGR⁵ consisting of —COOH and                tetrazol-5-yl.    -   wherein the compound of formula (I) is        (S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic        acid;    -   wherein the compound of formula (I) is (S)-sodium        3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate;    -   further comprising reacting said chiral acetylenic addition        product with an acid halide in a reaction medium to form a        chiral acetylenic ketone, wherein at least one of these        additional features applies:        -   a2) said reacting said chiral acetylenic addition product            with an acid halide is made in the presence of a            palladium-containing catalyst and Cu(I) catalyst;        -   a2) a base is added to said reaction medium;        -   a3) a base selected from the group consisting of            N-methylmorpholine, triethyl amine, 1,4-dimethylpiperazine,            diisopropylethyl amine, and mixtures thereof, is added to            said reaction medium;        -   a4) N-methylmorpholine is added to said reaction medium;        -   a5) N-methylmorpholine, a palladium-containing catalyst, and            a Cu(I) catalyst are added to said reaction medium;        -   a6) said acid halide is 3,4-dichlorobenzoyl chloride;        -   a7) said chiral acetylenic addition product is            2-m-tolyl-pent-4-ynoic acid 1-ethoxycarbonyl-ethyl ester;        -   a8) said chiral acetylenic ketone is            6-(3,4-dichloro-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acid            1-ethoxycarbonyl-ethyl ester;        -   a9) said compound of formula (I) is            (S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic            acid;

a10) said compound of formula (I) is (S)-sodium3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate.

Some embodiments include methods of making a compound of formula (I),enantiomers, diastereomers, racemics, pharmaceutically acceptable salts,esters, and amides thereof, comprising a condensation of a substitutedhydrazine and an acetylenic ketone to form a pyrazole derivative, saidpyrazole derivative having a pyrazole framework with one of the nitrogenmembers in said pyrazole framework substituted. In some embodiments,said condensation is a regioselective condensation. More specifically,additional embodiments include those methods wherein any one of thefollowing features applies:

-   -   said pyrazole derivative is formed with a regioisomeric excess        of at least about 80%;    -   said acetylenic ketone is a chiral acetylenic ketone and said        pyrazole derivative is a chiral pyrazole derivative;    -   said pyrazole derivative is a compound of formula P7′        wherein the substituent DER in P7′ is such that the group        C(═O)DER in P7′ is an ester group, in even more specific        embodiments wherein the Ar-attached carbon member is a        stereogenic center with two enantiomeric forms and one of said        two enantiomeric forms is in excess with respect to the other of        said enantiomeric forms, and in even more specific embodiments        wherein said enantiomer that is in excess is the (S) enantiomer;    -   said condensation is a regioselective condensation that        comprises mixing an inorganic base and said substituted        hydrazine with an acetylenic ketone in a reaction medium, and in        even more specific embodiments further comprising quenching said        reaction medium with an acidic solution to bring the pH of said        reaction medium to an acidic pH;    -   said condensation is a regioselective condensation that        comprises mixing an inorganic base and said substituted        hydrazine with an acetylenic ketone that is a chiral acetylenic        ketone in a reaction medium, and in even more specific        embodiments further comprising quenching said reaction medium        with an acidic solution to bring the pH of said reaction medium        to an acidic pH;    -   said condensation is a regioselective condensation that is        performed in a non-protic solvent;    -   said condensation is a regioselective condensation that is        performed in a non-protic solvent selected form the group        consisting of THF, TMF, ether, toluene, dichloromethane, and        mixtures thereof;    -   said condensation is a regioselective condensation that is        performed in THF;    -   said condensation is a regioselective condensation that        comprises mixing an inorganic base and said substituted        hydrazine with an acetylenic ketone in a reaction medium        comprising a non-protic solvent, and more specific embodiments        further comprising quenching said reaction medium with an acidic        solution to bring the pH of said reaction medium to an acidic        pH, in even more specific embodiments said pyrazole derivative        is an ester and further comprising hydrolyzing said ester to        form a pyrazole acid derivative, and in even more specific        embodiments further comprising forming a salt of said pyrazole        acid derivative, and in even more specific embodiments further        comprising crystallizing said salt of said pyrazole acid        derivative;    -   said condensation is a regioselective condensation that        comprises mixing an inorganic base and said substituted        hydrazine with an acetylenic ketone that is a chiral acetylenic        ketone in a reaction medium comprising a non-protic solvent, and        in more specific embodiments further comprising quenching said        reaction medium with an acidic solution to bring the pH of said        reaction medium to an acidic pH, in even more specific        embodiments said pyrazole derivative is a chiral pyrazole ester        derivative and further comprising hydrolyzing said ester to form        a chiral pyrazole acid derivative, and in even more specific        embodiments further comprising forming a chiral salt of said        chiral pyrazole acid derivative, and in even more specific        embodiments further comprising crystallizing said chiral salt of        said chiral pyrazole acid derivative;    -   said condensation is a regioselective condensation that is        performed in a protic solvent;    -   said condensation is a regioselective condensation that is        performed in a protic solvent selected from the group consisting        of water, alcohol, alcohol mixtures, carboxylic acid, and        mixtures thereof;    -   said condensation is a regioselective condensation that is        performed in a protic solvent selected from the group consisting        of methanol, ethanol, and mixtures thereof;    -   said condensation is a regioselective condensation that        comprises mixing an inorganic base and said substituted        hydrazine with an acetylenic ketone in a reaction medium        comprising a protic solvent, and in more specific embodiments        further comprising quenching said reaction medium with an acidic        solution to bring the pH of said reaction medium to an acidic        pH, in even more specific embodiments said pyrazole derivative        is an ester and further comprising hydrolyzing said ester, to        form a pyrazole acid derivative, and in even more specific        embodiments further comprising forming a salt of said pyrazole        acid derivative, and in even more specific embodiments further        comprising crystallizing said salt of said pyrazole acid        derivative;    -   said condensation is a regioselective condensation that        comprises mixing an inorganic base and said substituted        hydrazine with an acetylenic ketone that is a chiral acetylenic        ketone in a reaction medium comprising a protic solvent, in more        specific embodiments further comprising quenching said reaction        medium with an acidic solution to bring the pH of said reaction        medium to an acidic pH, in even more specific embodiments said        pyrazole derivative is a chiral pyrazole ester derivative, and        further comprising hydrolyzing said ester, to form a chiral        pyrazole acid derivative, and in even more specific embodiments        further comprising forming a chiral salt of said chiral pyrazole        acid derivative, and in even more specific embodiments further        comprising crystallizing said chiral salt of said chiral        pyrazole acid derivative;    -   said acetylenic ketone is        6-(3,4-dichloro-phenyl)-6-oxo2-m-tolyl-hex-4-ynoic acid        1-ethoxycarbonyl-ethyl ester;    -   said substituted hydrazine is a non-free base hydrazine, and in        more specific embodiments said non-free base hydrazine is        4-methoxyphenyl hydrazine.HCl;    -   said substituted hydrazine is a free base hydrazine, and in more        specific embodiments said free base hydrazine is 4-methoxyphenyl        hydrazine;    -   said pyrazole derivative is a mixture of a first pyrazole        derivative and a second pyrazole derivative, wherein said first        pyrazole derivative has the nitrogen-member substitution pattern        in the pyrazole framework specified by 1-(R¹)-1H-pyrazol, said        second pyrazole derivative has the nitrogen-member substitution        pattern in the pyrazole framework specified by        2-(R¹)-2H-pyrazol, and said first pyrazole derivative is        obtained in an amount that is greater than the amount of said        second pyrazole derivative;    -   said pyrazole derivative is a mixture of a first pyrazole        derivative and a second pyrazole derivative, wherein said first        pyrazole derivative has the nitrogen-member substitution pattern        in the pyrazole framework specified by 1-(R¹)-1H-pyrazol, said        second pyrazole derivative has the nitrogen-member substitution        pattern in the pyrazole framework specified by        2-(R¹)-2H-pyrazol, and said second pyrazole derivative is        obtained in an amount that is greater than the amount of said        first pyrazole derivative;    -   said pyrazole derivative is a mixture of a first pyrazole        derivative and a second pyrazole derivative, wherein said first        pyrazole derivative is        3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic        acid 1-ethoxycarbonyl-ethyl ester, said second pyrazole        derivative is        3-[5-(3,4-dichloro-phenyl)-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-2-m-tolyl-propionic        acid 1-ethoxycarbonyl-ethyl ester, and said first pyrazole        derivative is obtained in an amount that is greater than the        amount of said second pyrazole derivative;    -   said pyrazole derivative is a mixture of a first pyrazole        derivative and a second pyrazole derivative, wherein said first        pyrazole derivative is        3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic        acid 1-ethoxycarbonyl-ethyl ester, said second pyrazole        derivative is        3-[5-(3,4-dichloro-phenyl)-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-2-m-tolyl-propionic        acid 1-ethoxycarbonyl-ethyl ester, and said second pyrazole        derivative is obtained in an amount that is greater than the        amount of said first pyrazole derivative;    -   said pyrazole derivative is        3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic        acid 1-ethoxycarbonyl-ethyl ester, in more specific embodiments        further comprising hydrolyzing said ester to form the chiral        pyrazole acid derivative        (S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic        acid, in more specific embodiments further-comprising forming        the chiral salt (S)-CAT        3-[5-(3,4-dichlorophenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate,        wherein CAT is one of alkali metal and amine, in even more        specific embodiments further comprising crystallizing said        chiral salt to obtain a chiral product; in even more specific        embodiments said chiral pyrazol acid derivative is formed with        an S-enantiomeric excess ee(S) of at least about 80%, and in        even more specific embodiments said chiral product is obtained        with an S-enantiomeric excess ee(S) of at least about 99%;    -   the Ar attached carbon is saturated and has the configuration    -   the Ar attached carbon is unsaturated and has the configuration    -   Ar, optionally substituted with R^(r) as described above, is        selected from the group GAr as described above, in more specific        embodiments Ar, optionally substituted with R^(r) as described        above, is selected from the group PGAr as described above, and        specific Ar are selected from the group SGAr as described above;    -   there are 0, 1, or 2 R^(r) substituents;    -   R^(r) is selected from the group GR^(r) as described above, and        in more specific embodiments R^(r) is selected from the group        PGR^(r) as described above;    -   R⁵ is selected from the group GR⁵ as described above, and in        more specific embodiments R⁵ is selected from the group PGR⁵ as        described above;    -   R⁴ is selected from the group consisting of —H, —F and —CH₃, and        in more specific embodiments R⁴ is H;    -   n is 0 or 1;    -   R¹, optionally substituted with R^(p) as described above, is        selected from the group GR¹ as described above, in more specific        embodiments R¹, optionally substituted with R^(p) as described        above, is selected from the group PGR¹ as described above, and        in even more specific embodiments R¹ is selected from the group        SGR¹ as described above;    -   R^(p) is selected from the group GR^(p) as described above, and        in more specific embodiments R^(p) is selected from the group        PGR^(p) as described above;    -   R², optionally substituted with R^(q) as described above, is        selected from the group GR² as described above, in more specific        embodiments R², optionally substituted with R^(q) as described        above, is selected from the group PGR² as described above, and        in even more specific embodiments R² is selected from the group        SGR² as described above;    -   R^(q) is selected from the group GR^(q) as described above, and        in more specific embodiments R^(q) is selected from the group        PGR^(q) as described above;    -   there are 0, 1, or 2 R^(q) substituents;    -   R³ is selected from the group consisting of —H, —F, Cl, Br and        —CH₃, and in more specific embodiments R³ is H;    -   the compound of formula (I) is        (S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic        acid;    -   the compound of formula (I) is (S)-sodium        3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate.

Some embodiments include methods of making a compound of formula (I),enantiomers, diastereomers, racemics, pharmaceutically acceptable salts,esters, and amides thereof, comprising: crystallizing a salt of thepyrazole acid derivative of formula (I-A)

out of a medium to form a crystallization product, wherein said mediumbefore said crystallizing contains an amount of said salt of saidpyrazole acid derivative, said medium contains a water amount, andwherein said water amount is within about 20% of the water amountequimolar with said amount of said salt. More specifically additionalembodiments include those methods wherein any one of the followingfeatures applies:

-   -   said pyrazole acid derivative (I-A) is a compound of formula        (P8′)    -   said salt before said crystallizing has an enantiomeric excess        of at least 80% and said crystallization product has an        enatiomeric excess of at least 90%, and in even more specific        embodiments, said crystallization product is enantiomerically        pure;    -   said salt before crystallizing has a regioisomeric excess of at        least 80% and said crystallization product has a regioisomeric        excess of at least 90%, and in even more specific embodiments,        said crystallization product has a regioisomeric excess of at        least 90%;    -   said salt before said crystallizing has an enantiomeric excess        of at least 80% and a regioisomeric excess of at least 80%, and        said crystallization product has an enatiomeric excess of at        least 90% and a regiosisomeric excess of at least 90%, and in        even more specific embodiments, said crystallization product is        enantiomerically pure and has a regioisomeric excess of at least        99%;    -   the Ar attached carbon is saturated and has the configuration    -   the Ar attached carbon is unsaturated and has the configuration    -   Ar, optionally substituted with R^(r) as described above, is        selected from the group GAr as described above, in more specific        embodiments Ar, optionally substituted with R^(r) as described        above, is selected from the group PGAr as described above, and        specific Ar are selected from the group SGAr as described above;    -   there are 0, 1, or 2 R^(r) substituents;    -   R^(r) is selected from the group GR^(r) as described above, and        in more specific embodiments R^(r) is selected from the group        PGR^(r) as described above;    -   R⁴ is selected from the group consisting of —H, —F and —CH₃, and        in more specific embodiments R⁴ is H;    -   n is 0 or 1;    -   R¹, optionally substituted with R^(p) as described above, is        selected from the group GR¹ as described above, in more specific        embodiments R¹, optionally substituted with R^(p) as described        above, is selected from the group PGR¹ as described above, and        in even more specific embodiments R¹ is selected from the group        SGR¹ as described above;    -   R^(p) is selected from the group GR^(p) as described above, and        in more specific embodiments R^(p) is selected from the group        PGR^(p) as described above;    -   R², optionally substituted with R¹ as described above, is        selected from the group GR² as described above, in more specific        embodiments R², optionally substituted with R^(q) as described        above, is selected from the group PGR² as described above, and        in even more specific embodiments R² is selected from the group        SGR² as described above;    -   R^(q) is selected from the group GR^(q) as described above, and        in more specific embodiments R^(q) is selected from the group        PGR^(q) as described above;    -   there are 0, 1, or 2 R^(q) substituents;    -   R³ is selected from the group consisting of —H, —F, Cl, Br and        —CH₃, and in more specific embodiments R³ is H;    -   the compound of formula (I) is        (S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic        acid;    -   the compound of formula (I) is (S)-sodium        3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate;    -   said pyrazole acid derivative and said salt are chiral;    -   said pyrazole acid derivative comprises a mixture of        regioisomers with respect to the substitution of the nitrogen        members in the pyrazole framework of said pyrazole acid        derivative, and in more specific embodiments said mixture of        regioisomers comprises two regioisomers that are chiral;    -   said pyrazole acid derivative comprises        (S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic        acid;    -   said water amount is within about 10% of the water amount        equimolar with said salt;    -   said water amount is within 5% of the water amount equimolar        with said salt;    -   said water amount is about equimolar with said salt;    -   said medium comprises a solvent component in which said salt is        soluble and another component in which said salt is less soluble        than in said solvent component;    -   said medium comprises a solvent component in which said salt is        soluble, said solvent component comprising a solvent being        selected form the group consisting of THF, MeOH, CH₂Cl₂, and        mixtures thereof, and another component in which said salt is        less soluble than in said solvent component, said another        component being selected from the group consisting of CH₃CN,        toluene, hexane, and mixtures thereof;    -   said medium comprises a solvent component in which said salt is        soluble, said solvent component comprising THF, and another        component in which said salt is less soluble than in said        solvent component, said another component comprising CH₃CN;    -   said salt is chiral, said crystallizing leads to a chiral        separated product, and the enantiomeric excess of said separated        product is at least 90%;    -   said salt is chiral, said crystallizing leads to a chiral        separated product, and said chiral separated product is        enantiomerically pure;    -   said water amount is within 5% of the water amount equimolar        with said salt, said medium comprises a solvent component in        which said salt is soluble, said solvent component comprising        THF, and another component comprising CH₃CN;    -   said salt is an alkali metal salt, and in more specific        embodiments said salt is one of sodium salt and potassium salt;    -   said salt is an amine salt, and in more specific embodiments        said salt is one of meglumine salt, tromethamine salt,        tributylamine salt, S-alpha-methylbenzyl amine, and ethylene        diamine salt;    -   said water amount is within 5% of the water amount equimolar        with said salt, said medium comprises a solvent component in        which said salt is soluble, said solvent component comprising        THF, said another component comprising CH₃CN, and said salt        being (S)-sodium        3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate.

Some embodiments include products, enantiomers, diastereomers, racemics,pharmaceutically acceptable salts, esters, and amides thereof, obtainedby a method comprising: crystallizing a salt of the pyrazole acidderivative of formula (I-A)

out of a medium, wherein said medium contains an amount of said salt ofsaid pyrazole acid derivative, said medium contains a water amount, andwherein said water amount is within about 20% of the water amountequimolar with said amount of said salt. More specifically additionalembodiments include those products obtained by crystallization methodswherein any one of the features referred to herein for thecrystallization of a salt of the pyrazole acid derivative of formula(I-A) applies.

Referring to Scheme Q, there are disclosed the following notes andadditions. Acetylenic ketone Q2 is obtained by coupling suitablysubstituted acid halide P4 with Q1 as described in Scheme Q. Thiscoupling is performed in some embodiments of this invention by aSonogashira reaction as described in Scheme P.

“Est” is an ester group, such as C(O)(Rox), where Rox is preferably aC₁₋₄alkoxy, wherein “C₁₋₄” denotes herein a linear or branched chain forsaid alkoxy, such as ethoxy. Compound Q1 is either available or it canbe prepared by alkylation as described in Scheme P.

Condensation with a suitably substituted hydrazine P6 is performed asindicated in Scheme P to obtain racemic product Q3. As indicated in thecontext of Scheme P, compounds with a nitrogen substitution pattern inthe pyrazole frameowrk as shown in Q3 in the surrounding chemicalenvironment of compounds of this invention can be produced by thisreaction with high regioselectivity, which reached in embodiments ofthis invention at least about 80%, or a molar ratio of 1:4, with theisomer in excess being the isomer with the pyrazole frameworksubstituted as shown in Scheme Q. Chiral product Q8 is obtained from Q3,preferably by enzymatic resolution Q4.

Enzymatic resolution of compounds Q3 was developed in the context ofthis invention. It was found in the context of this invention thatcompounds Q3 could be enzymatically resolved to achieve an enantiomericexcess of at least 90% with an enzyme suitable for hydrolyzing oneenantiomer (for example enantiomer (S)) while leaving the otherenantiomer (for example enantiomer (F)) esterified. Embodiments of thisenzymatic resolution utilized an enzyme comprising a lipase. Examples oflipases include Mucor miehei, lyo; Rhizomucor miehei; and Candidacyclindracea, of which Mucor miehei, lyo, is the preferred lipase.Commercial lipase products used in embodiments of this invention areknown as Altus catalyst #8. The enzyme was used in a buffered mediummixed with solutions of compound Q3 in a suitable solvent, such asisopropyl alcohol/toluene. Enzymatic resolution quenching and separationof resolution products lead to product Q8.

When one enantiomer in a mixture of enantiomers is to be enriched, forexample when the S-enantiomer is the desired stereospecific form of Q8,the other enantiomer-rich fraction, for example the R-enantiomerenriched fraction, is preferably racemized and incorporated into theprocess as product Q3 that is subject to enzymatic resolution Q4.Racemization is accomplished, for example, by adding a base, such asKHMDS (potassium bis(trimethylsilyl)amide, also known as potassiumhexamethyldisilazide), to a solution of the ester to be racemized (theR-enantiomer enriched ester in some embodiments of this invention).

Preferred bases include bases whose pK_(a) is greater than about 23, andmore preferably greater than about 25. One of ordinary skill in the artwill recognize in light of this disclosure that the use of a base whosepK_(a) is chosen according to the direction provided herein will causethe removal of a proton from the stereogenic center and that subsequentreprotonation at the same center will result in racemization of theester.

Racemization quenching and product separation lead to racemates that canbe incorporated in the enzymatic resolution through a recycling process.This recycling process comprises at least one cycle of racemization andenzymatic resolution. The implementation of this recycling step (notdisplayed in Scheme Q) leads to a quantitatively improved recovery ofthe desired enantiomer.

As indicated in Scheme P with respect to P8, product Q8 can be furtherpurified by crystallization. Embodiments of this invention lead to theproduction of the a salt form of Q8 with ee(S)≧99.9%. In someembodiments of this invention, Q1 was 2-m-tolyl-pent-4-ynoic acid ethylester, Q2 was 6-(3,4-dichloro-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acidethyl ester, Q3 was3-15-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid ethyl ester, and Q8 was(S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid, or a salt thereof, such as (S)-sodium3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate.

Embodiments of processes schematically illustrated in Scheme Q comprisea 3-step convergent synthesis of a pyrazole framework from acetylenicketone Q2 by a regioselective condensation. An additional step ofenzymatic resolution Q4 comprises kinetic resolution throughenzyme-catalyzed hydrolysis of a racemic ester with the pyrazoleframework incorporated therein. Optical purity following enzymaticresolution Q4 in embodiments of this invention was at least 92%(ee >92%). Embodiments of such 4-step synthesis according to the presentinvention contrast with other synthetic approaches that rely on at leasteight synthetic steps.

Some embodiments include methods of making a compound of formula (I),enantiomers, diastereomers, racemics, pharmaceutically acceptable salts,esters, and amides thereof, comprising: enzymatically resolving with alipase a esterified pyrazole derivative of formula (Q3′)

wherein the Ar attached carbon forms a stereogenic center, Est is asubstituent chosen from the definition of R⁵ such that Est is acarboxylic acid ester group. More specifically, additional embodimentsinclude those methods wherein any one of the following features applies:

-   -   the Ar attached carbon in one of the enantiomers of compound        (Q3′) has the configuration    -   Ar, optionally substituted with R^(r) as described above, is        selected from the group GAr as described above, in more specific        embodiments Ar, optionally substituted with R^(r) as described        above, is selected from the group PGAr as described above, and        specific Ar are selected from the group SGAr as described above;    -   there are 0, 1, or 2 R^(r) substituents;    -   R^(r) is selected from the group GR^(r) as described above, and        in more specific embodiments R^(r) is selected from the group        PGR^(r) as described above;    -   R⁴ is selected from the group consisting of —H, —F and —CH₃, and        in more specific embodiments R⁴ is H;    -   n is 0 or 1;    -   R¹, optionally substituted with R^(p) as described above, is        selected from the group GR¹ as described above, in more specific        embodiments R¹, optionally substituted with R^(p) as described        above, is selected from the group PGR¹ as described above, and        in even more specific embodiments R¹ is selected from the group        SGR¹ as described above;    -   R^(p) is selected from the group GR^(p) as described above, and        in more specific embodiments R^(p) is selected from the group        PGR^(p) as described above;    -   R², optionally substituted with R^(q) as described above, is        selected from the group GR² as described above, in more specific        embodiments R², optionally substituted with R^(q) as described        above, is selected from the group PGR² as described above, and        in even more specific embodiments R² is selected from the group        SGR² as described above;    -   R^(q) is selected from the group GR^(q) as described above, and        in more specific embodiments R^(q) is selected from the group        PGR^(q) as described above;    -   there are 0, 1, or 2 R^(q) substituents;    -   R³ is selected from the group consisting of —H, —F, Cl, Br and        —CH₃, and in more specific embodiments R³ is H;    -   the compound of formula (I) is        (S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic        acid;    -   the compound of formula (I) is (S)-sodium        3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate;    -   said compound (Q3′) comprises a mixture of regioisomers with        respect to the substitution of the nitrogen members in the        pyrazole framework of said compound (Q3′);    -   said enzymatically resolving leads to a chiral resolution        product, and the enantiomeric excess of said resolution product        is at least 90%;    -   said enzymatically resolving is performed with an enzyme        comprising a lipase that preferentially hydrolyzes enantiomer S        of said compound of formula (Q3′);    -   said enzymatically resolving is performed with an enzyme        comprising a lipase selected form the group consisting of Mucor        miehei, lyo; Rhizomucor miehei; Candida cyclindracea; and        mixtures thereof;    -   said enzymatically resolving is performed with lipase Mucor        miehei, lyo;    -   said enzymatically resolving is performed with Altus catalyst        #8;    -   further comprising enzymatic resolution quenching and separation        of a resolution product to form at least two fractions, a first        fraction comprising said resolution product with an excess of a        first enantiomer with respect to a second enantiomer, and a        second fraction comprising a product with an excess of said        second enantiomer with respect to said first enantiomer, and in        more specific embodiments said first enantiomer is the S        enantiomer and said second enantiomer is the R enantiomer;    -   further comprising enzymatic resolution quenching and separation        of a resolution product to form at least two fractions, a first        fraction comprising said resolution product with an excess of a        first enantiomer with respect to a second enantiomer, and a        second fraction comprising a product with an excess of said        second enantiomer with respect to said first enantiomer, and        racemazing said second fraction to form a recycle fraction, in        more specific embodiments further comprising enzymatically        resolving said recycle fraction, wherein said racemazing and        said enzymatically resolving define a recycling, in more        specific embodiments said recycling is peformed at least once,        in more specific embodiments said racemazing is performed by        mixing said second fraction with a base, in still more specific        embodiments, said base is a base with a pK_(a) greater than 23,        and in still more specific embodiments, said base comprises        potassium bis(trimethylsilyl)amide;    -   further comprising enzymatic resolution quenching and separation        of a resolution product to form at least two fractions, a first        fraction comprising said resolution product with an excess of a        first enantiomer with respect to a second enantiomer, said first        enantiomer being in the form of a pyrazole acid derivative and        said second enantiomer being in the form of a pyrazole ester        derivative, in more specific embodiments further comprising        forming a salt of said pyrazole acid derivative enantiomer, and        in still more specific embodiments further comprising        crystallizing said salt;    -   further comprising enzymatic resolution quenching and separation        of a resolution product to form at least two fractions, a first        fraction comprising said resolution product with an excess of a        first enantiomer with respect to a second enantiomer, said first        enantiomer being        (S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic        acid;    -   further comprising enzymatic resolution quenching and separation        of a resolution product to form at least two fractions, a first        fraction comprising said resolution product with an excess of a        first enantiomer with respect to a second enantiomer, said first        enantiomer being        (S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic        acid, in more specific embodiments further comprising forming        the salt (S)-sodium        3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate,        and in still more specific embodiments further comprising        crystallizing said salt.

Referring to Scheme R, there are disclosed the following notes andadditions. In some embodiments of this invention, a specificstereoisomer was obtained by stereoselective enolate alkylation of aproduct of condensation with a substituted hydrazine. Regioselectivecondensation was performed in some embodiments between a substitutedhydrazine and a β-diketone, such as R4 that shows a β-diketone in itsenol form. Reference herein to one tautomer of any compound that canexist in more than one tautomeric form includes a reference to any othertautomeric form that is not explicitly referred to. For example,reference to structure R4 in an enol form (as shown in Scheme R) alsorefers to the same structure in its keto form.

Amide R2 is obtained from acid halide P4 and amine R1. Substituents R′and R″ are independently chosen, preferably as C₁₋₄alkyl, and mostpreferably R′ is CH₃ and R″ is CH₃.

Amide R2 reacts with acetylenic ether R3 to form acetylenic ketone R4.1,which reacts with amine R2′ to form β-enaminoketone R4.2 which, underacidic conditions hydrolyzes in situ to β-diketone R4, shown in Scheme Rin its enol form. Regioselective condensation produces R5.1 which can bedeprotected as in Depr in Scheme R, to form pyrazole alcohol R5.

Amide R2 is preferably prepared through a controlled temperature quenchthat generates, in addition to R2, amine R2′. Acetylenic ketone R4.1 ispreferably obtained by propargylating R2 and subsequently quenching theraction mixture with an acidic substance at about 0° C. The acidicsubstance is chosen so that it preferably comprises a chemicallycompatible acid capable of regulating the medium pH to a moderatelyacidic value, such as to an aqueous layer pH of about 5.

In other embodiments of this invention, quenching is performed with asaturated aqueous solution of ammonium chloride. In these embodiments,R2 converts to an amine, such as β-aminoketone R4.3:

This amine, and also β-enaminoketone R4.2, also participate in thecondensation reaction with suitably substituted hydrazine P6 asdescribed herein to form R5.1 in a high regioselectivity process.

Substituent P′ in R3 is preferably a heterocyclic ring attached by a Cthat is next to a heteroatom, more preferably the heterocyclic ring hasonly one heteroatom, most preferably this heteroatom is O and P′ istetrahydropyranyl (THP). Any other suitable protecting group that cansubsequently be removed in a deprotection step can be used as P′. GroupsP′ that form ethers OP′ are preferred groups.

β-Enaminoketone R4.2 is formed in situ in the addition of amine R2′ toacetylenic ketone R4.1. The enamino group in R4.2 undergoes in situhydrolysis under aqueous acidic conditions to form β-diketone R4, shownin Scheme R in its enol form. Analysis of the reaction layer (organiclayer) reveals that R4 predominates over R4.1. In embodiments of thisinvention the molar ratio of the amount of R4.1 to the amount of R4 inthe mixture was about 5:95, respectively. The species in this mixture donot need isolation for further processing. Suitably substitutedhydrazine P6 in other than a free base form and an inorganic base areadded to this mixture to form pyrazole derivative R5. 1. An example ofP6 in non-free base form is a suitably substituted hydrazinehydrochloride. As indicated herein for this condensation, a carbonate isa preferred inorganic base. It was found in the context of thisinvention that this pyrazole derivative formation achieves highregioselectivity of, in some embodiments, at least 90%, and in someembodiments at least 95%, with R5.1 (one regioisomer, with nitrogensubstitution pattern 1-(R¹)-1H-pyrazol) being formed preferentially withrespect to the pyrazole derivative that has R¹ as a substituent in thenitrogen member of the pyrazole framework shown unsusbstituted in SchemeR (the other regioisomer, with nitrogen substitution pattern2-(R¹)-2H-pyrazol). The molar ratio in embodiments of this inventionreferring to the ratio of the amount of R5.1 to the amount of the otherregioisomer (not shown in Scheme R) was about 98:2. The condensationreaction with hydrazine P6 is thought to take place with R4 and alsowith R4.2, and furthermore with R4.3 when this substance is present.

Suitably substituted hydrazine P6 is used in some embodiments of thisinvention in a free base form. When the suitably substituted hydrazineP6 is in free base form, the isomer with the nitrogen substitutionpattern in the pyrazole framework that corresponds to the2-(R¹)-2H-pyrazol substitution (not shown in Scheme R) is preferentiallyformed. No inorganic base is preferably used in such embodiments with ahydrazine in free base form.

Pyrazole derivative R5.1 undergoes deprotection to generate pyrazolealcohol R5. When P′ is THP, this deprotection is preferably performed byusing tosic acid in an alcoholic medium, such as methanol.

Pyrazole alcohol R5 can be isolated or it can be maintained in solutionand converted to R6, where substituent X′ is a suitable substituent forthe stereoselective alkylation with G1 to form R7 as described in schemeG. X′ is preferably halo, more preferably Br or I, and most preferablyI, in which case R5 is halogenated to R6.

In embodiments in which pyrazole alcohol R5 is isolated, such isolationis preferentially performed by precipitation from a low polarity medium,such as heptane. Halogenation of R5 can be achieved by converting thehydroxyl group with a suitable reagent to a leaving group in ahalogenation step, such as by mesylation of the alcohol and subsequentreaction with iodide or bromide.

Halogenated pyrazole derivative R6 can be isolated as shown in Scheme R.Such isolation is not needed in some embodiments, in which R6 is kept inthe organic medium for stereoselective alkylation. Halogenated pyrazolederivative R6 is the alkylating agent that reacts with derivative G1 toform chiral R7. This chiral compound R7 does not require its isolationfor further processing, and it is subject in embodiments of thisinvention to an oxidative hydrolysis and acidification to yield pyrazoleacid R8.

G1 is obtained in embodiments of this invention from an acid, such as

and a chiral tetrahydro-indeno-oxazole in the presence of an organicbase, such as triethylamine, and an activating agent. A preferredactivating agent is pivaloyl chloride. A preferred organic solvent forthis reaction is a low polarity solvent, such as toluene.

As indicated in Scheme R by the symbols within parenthesis, R7 isconverted to R8 analogously as G2 is converted to G3 according to SchemeG. Product R8 can further be purified as described above. Also asindicated in Scheme R by the symbols within parenthesis, R6 is in someembodiments obtained from R5 by halogenation, and A7 is obtained from A4or A6 by halogenation as shown in Scheme A.

As described herein, R8 salts can be prepared (not shown in Scheme R).Inorganic and organic salts of R8, such as alkali metal salts and aminesalts, were prepared in embodiments of this invention. Also as describedherein, it was found in the context of this invention that these saltscan be isolated by crystallization, and that embodiments of suchcrystallization are crystalline material, and other embodiments comprisea mixture of crystalline and amorphous material, the latter embodimentsbeing referred to as being semicrystalline.

Some embodiments include methods of making a compound of formula (I),enantiomers, diastereomers, racemics, pharmaceutically acceptable salts,esters, and amides thereof, comprising: a condensation of a substitutedhydrazine and at least one of a β-diketone, a β-enaminoketone, and aβ-aminoketone to form a pyrazole derivative, said pyrazole derivativehaving a pyrazole framework with one of the nitrogen members in saidpyrazole framework substituted. In some embodiments said condensation isa regioselective condensation. More specifically, additional embodimentsinclude those methods wherein any one of the following features applies:

-   -   said β-diketone comprises a compound of formula R4:        wherein R² is defined above and P′ is a protecting group that        can be removed to form a hydroxyl group, in more specific        embodiments P′ is a group such that OP′ is an ether group, and        in even more specific embodiments P′ is THP;    -   said β-enaminoketone comprises a compound of formula R4.2:        wherein R² is defined above, P′ is a protecting group that can        be removed to form a hydroxyl group, and R′ and R″ are        independently chosen from the group of C₁₋₄alkyl groups, in more        specific embodiments P′ is a group such that OP′ is an ether        group, in even more specific embodiments P′ is THP, and in other        more specific embodiments each one of R′ and R″ is methyl;    -   said β-aminoketone comprises a compound of formula R4.3:        wherein R² is defined above and P′ is a protecting group that        can be removed to form a hydroxyl group, in more specific        embodiments P′ is a group such that OP′ is an ether group, and        in even more specific embodiments P′ is THP;    -   said substituted hydrazine is a non-free base hydrazine, and in        more specific embodiments said non-free base hydrazine is        4-methoxyphenyl hydrazine.HCl;    -   said substituted hydrazine is a free base hydrazine, and in more        specific embodiments said free base hydrazine is 4-methoxyphenyl        hydrazine;    -   said pyrazole derivative is formed with a regioisomeric excess        of at least about 90%, and in more specific embodiments said        pyrazole derivative is formed with a regioisomeric excess of at        least about 95%;    -   said pyrazole derivative is a mixture of a first pyrazole        derivative and a second pyrazole derivative, wherein said first        pyrazole derivative has the nitrogen-member substitution pattern        in the pyrazole framework specified by 1-(R¹)-1H-pyrazol, said        second pyrazole derivative has the nitrogen-member substitution        pattern in the pyrazole framework specified by        2-(R¹)-2H-pyrazol, and said first pyrazole derivative is        obtained in an amount that is greater than the amount of said        second pyrazole derivative;    -   said pyrazole derivative is a mixture of a first pyrazole        derivative and a second pyrazole derivative, wherein said first        pyrazole derivative has the nitrogen-member substitution pattern        in the pyrazole framework specified by 1-(R¹)-1H-pyrazol, said        second pyrazole derivative has the nitrogen-member substitution        pattern in the pyrazole framework specified by        2-(R¹)-2H-pyrazol, and said second pyrazole derivative is        obtained in an amount that is greater than the amount of said        first pyrazole derivative;    -   said pyrazole derivative is a mixture of a first pyrazole        derivative and a second pyrazole derivative, wherein said first        pyrazole derivative is        [5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-methanol,        said second pyrazole derivative is        [5-(3,4-dichloro-phenyl)-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-methanol,        and said first pyrazole derivative is obtained in an amount that        is greater than the amount of said second pyrazole derivative;    -   said pyrazole derivative is a mixture of a first pyrazole        derivative and a second pyrazole derivative, wherein said first        pyrazole derivative is        [5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-methanol,        said second pyrazole derivative is        3-[5-(3,4-dichloro-phenyl)-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-methanol,        and said second pyrazole derivative is obtained in an amount        that is greater than the amount of said first pyrazole        derivative;    -   said pyrazole derivative is a pyrazole alcohol derivative of        formula (R5′)    -   said pyrazole derivative is a pyrazole alcohol derivative of        formula (R5′)        and further comprising halogenating said pyrazole alcohol        derivative to replace the hydroxyl group in said pyrazole        alcohol derivative by a halo group to form a compound of formula        (R6′)        wherein substituent X′ is said halo group, and in more specific        embodiments said halo group is one in the group of bromo and        iodo;    -   said pyrazole derivative is a pyrazole alcohol derivative of        formula (R5′)        further comprising halogenating said pyrazole alcohol derivative        to replace the hydroxyl group in said pyrazole alcohol        derivative by a halo group to form a compound of formula (R6′)        wherein substituent X′ is said halo group, and further        comprising alkylating a chiral agent with said compound of        formula (R6′) as an alkylating agent, in more specific        embodiments said chiral agent being a chiral        tetrahydro-indeno-oxazole derivative, in even more specific        embodiments said chiral tetrahydro-indeno-oxazole derivative        being formed from an acid        and a chiral tetrahydro-indeno-oxazole in the presence of an        organic base and an activating agent, in even more specific        embodiments said activating agent being pivaloyl chloride, and        in even more specific embodiments said chiral        tetrahydro-indeno-oxazole derivative is formed in a medium that        comprises a low polarity solvent, and in even more specific        embodiments said R5′ is        [5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-methanol,        said R6′ is        [5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole, said        acid is m-tolylacetic acid, said chiral        tetrahydro-indeno-oxazole derivative is        3-(2-m-tolyl-acetyl)-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one,        said chiral tetrahydro-indeno-oxazole is        (3aS-cis)-(−)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]-oxazol-2-one;    -   said pyrazole derivative is a pyrazole alcohol derivative of        formula (R5′)        further comprising halogenating said pyrazole alcohol derivative        to replace the hydroxyl group in said pyrazole alcohol        derivative by a halo group to form a compound of formula (R6′)        wherein substituent X′ is said halo group, and further        comprising alkylating a chiral agent with said compound of        formula (R6′) as an alkylating agent to form a chiral pyrazole        derivative, in more specific embodiments said chiral agent being        a chiral tetrahydro-indeno-oxazole derivative, in even more        specific embodiments further comprising an oxidative hydrolysis        and acidification of said chiral pyrazole derivative to form a        chiral pyrazole acid derivative of formula (R8′)        wherein the Ar-attached carbon member in (R8′) is a saturated        stereogenic center, in even more specific embodiments forming a        salt of said pyrazole acid derivative (R8′), and in even more        specific embodiments crystallizing said salt, and in even more        specific embodiments said R5′ is        [5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-methanol,        said R6′ is        [5-(3,4-dichlorophenyl)-3-iodomethyl-1-(4-methoxyphenyl)-1H-pyrazole,        said acid is m-tolylacetic acid, said chiral        tetrahydro-indeno-oxazole derivative is        3-(2-m-tolyl-acetyl)-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one,        said chiral tetrahydro-indeno-oxazole is        (3aS-is)-(−)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]-oxazol-2-one,        said R8′ is        (S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic        acid, and said salt of said pyrazole acid derivative is        (S)-sodium        3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate;    -   wherein said β-diketone is obtained from an acidic hydrolysis of        a β-enaminoketone;    -   wherein said β-diketone is obtained from an acidic hydrolysis of        a β-enaminoketone, said β-enaminoketone is obtained form an        addition of an amine and an acetylenic ketone;    -   wherein said β-diketone is obtained from an acidic hydrolysis of        a β-enaminoketone, said β-enaminoketone is obtained form an        addition of an amine and an acetylenic ketone, and said        acetylenic ketone is obtained from a propargylation of an amide        and acidic quenching of said propargylation, in even more        specific embodiments, said β-diketone is        (Z)-1-(3,4-dichlorophenyl)-3-hydroxy-4-[(tetrahydro-2H-pyran-2-yl)oxy]-2-buten-1-one,        said β-enaminoketone is        (E)-1-(3,4-dichlorophenyl)-3-methoxymethylamino-4-[(tetrahydro-2H-pyran-2-yl)oxy]-2-buten-1-one,        said amide is 3,4-dichloro-N-methoxy-N-methyl-benzamide, said        amine is N-methoxymethylamine, said acetylenic ketone is        1-(3,4-dichlorophenyl)-4-[(tetrahydro-2H-pyran-2-yl)oxy]-2-butyn-1-one,        and said propargylation is performed with        tetrahydro-2-(2-propynyloxy)-2H-pyran;    -   wherein said β-aminoketone is obtained from a propargylation of        an amide and quenching of said propargylation with a saturated        aqueous solution of ammonium chloride;    -   wherein said β-diketone is obtained from an acidic hydrolysis of        a β-enaminoketone, said β-enaminoketone is obtained form an        addition of an amine and an acetylenic ketone, said acetylenic        ketone is obtained from a propargylation of an amide and acidic        quenching of said propargylation, and said amide is obtained in        an amide formation reaction of a first amine and an acid        chloride, and in even more specific embodiments, said first        amine is N,O-dimethylhydroxylamine hydrochloride, and said acid        chloride is 3,4-dichlorobenzoyl-chloride;    -   wherein said β-aminoketone is obtained from a propargylation of        an amide and quenching of said propargylation with a saturated        aqueous solution of ammonium chloride, and said amide is        obtained in an amide formation reaction of an amine and an acid        chloride;    -   the Ar attached carbon is saturated and has the configuration    -   the Ar attached carbon is unsaturated and has the configuration    -   Ar, optionally substituted with R^(r) as described above, is        selected from the group GAr as described above, in more specific        embodiments Ar, optionally substituted with R^(r) as described        above, is selected from the group PGAr as described above, and        specific Ar are selected from the group SGAr as described above;    -   there are 0, 1, or 2 R^(r) substituents;    -   R^(r) is selected from the group GR^(r) as described above, and        in more specific embodiments R^(r) is selected from the group        PGR^(r) as described above;    -   R⁵ is selected from the group GR⁵ as described above, and in        more specific embodiments R⁵ is selected from the group PGR⁵ as        described above;    -   R⁴ is selected from the group consisting of —H, —F and —CH₃, and        in more specific embodiments R⁴ is H;    -   n is 0 or 1;    -   R¹, optionally substituted with R^(p) as described above, is        selected from the group GR¹ as described above, in more specific        embodiments R¹, optionally substituted with R^(p) as described        above, is selected from the group PGR¹ as described above, and        in even more specific embodiments R¹ is selected from the group        SGR¹ as described above;    -   R^(p) is selected from the group GR^(p) as described above, and        in more specific embodiments R^(p) is selected from the group        PGR^(p) as described above;    -   R², optionally substituted with R^(q) as described above, is        selected from the group GR² as described above, in more specific        embodiments. R², optionally substituted with R^(q) as described        above, is selected from the group PGR² as described above, and        in even more specific embodiments R² is selected from the group        SGR² as described above;    -   R^(q) is selected from the group GR^(q) as described above, and        in more specific embodiments R^(q) is selected from the group        PGR^(q) as described above;    -   there are 0, 1, or 2 R^(q) substituents;    -   R³ is selected from the group consisting of —H, —F, Cl, Br and        —CH₃, and in more specific embodiments R³ is H;    -   the compound of formula (I) is        (S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic        acid;    -   the compound of formula (I) is (S)-sodium        3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate.

Referring to Scheme S, there are disclosed the following notes andadditions. A product of the addition of acetylenic ester Q1 to amide R2is regioselectively condensed with suitably substituted hydrazine P6 toform racemic Q3.

Q1 can be obtained by propargylation of the corresponding esterAr—CH₂-Est. In some embodiments, the reaction of Q1 with R2 is quenchedwith a saturated aqueous solution of ammonium chloride and then theorganic layer is treated with P6 to regioselectively form racemic Q3.

Scheme S shows another strategy for forming species that will condensewith a suitably substituted hydrazine in a high regioselective process.The nitrogen substitution in the pyrazole framework as shown in Q3 inScheme S was in embodiments of this invention in a molar ratio of about98:2 referring to the amount of the isomer shown in Q3 with respect tothe isomer that would have the substituent R¹ in the nitrogen memberthat is shown unsubstituted in Q3.

Substituent Est is defined above. Regioselective condensation withsuitably substituted hydrazine P6 according to Schemes R and S isperformed under conditions similar to those described in Schemes P andQ. Compound S8 is obtained by enzymatic resolution Q4 as described inScheme Q.

Some embodiments include methods of making a compound of formula (I),enantiomers, diastereomers, racemics, pharmaceutically acceptable salts,esters, and amides thereof, comprising: an addition of an acetylenicester to an amide to form an addition product, and a condensation ofsaid addition product with a substituted hydrazine to form a pyrazoleester derivative of formula Q3′

wherein the group Est in Q3′ is a substituent chosen from the definitionof R⁵ such that Est is a carboxylic acid ester group. In someembodiments said condensation is a regioselective condensation. Morespecifically, additional embodiments include those methods wherein anyone of the following features applies:

-   -   said pyrazole derivative is formed with a regioisomeric excess        of at least about 90%;    -   said pyrazole ester derivative is a racemic;    -   further comprising quenching said addition with a saturated        aqueous solution of ammonium chloride;    -   wherein said pyrazole ester derivative is a racemic and further        comprising enzymatically resolving said racemic, in more        specific embodiments, said enzymatically resolving is performed        with a lipase to form a chiral pyrazole acid derivative of        formula (P8′),        wherein the Ar-attached carbon member in P8′ is a stereogenic        center and one of the enantiomers of said stereogenic center is        in excess with respect to the other enantiomer, in even more        specific embodiments further comprising forming a salt of said        pyrazole acid derivative, in even more specific embodiments        further comprising crystallizing said salt of said pyrazole acid        derivative, in even more specific embodiments, said        enzymatically resolving is performed so that at least one of the        features given above for an enzymatic resolution with a lipase        applies, and in even more specific embodiments, said        crystallizing is performed so that at least one of the features        given above for crystallizing a salt of a pyrazole acid        derivative applies;    -   further comprising obtaining said acetylenic ester by        propargylating an ester    -   said amide is 3,4-dichloro-N-methoxy-N-methyl-benzamide;    -   said substituted hydrazine is a non-free base hydrazine, and in        more specific embodiments said non-free base hydrazine is        4-methoxyphenyl hydrazine.HCl;    -   said substituted hydrazine is a free base hydrazine, and in more        specific embodiments said free base hydrazine is 4-methoxyphenyl        hydrazine;    -   said pyrazole derivative is a mixture of a first pyrazole        derivative and a second pyrazole derivative, wherein said first        pyrazole derivative has the nitrogen-member substitution pattern        in the pyrazole framework specified by 1-(R¹)-1H-pyrazol, said        second pyrazole derivative has the nitrogen-member substitution        pattern in the pyrazole framework specified by        2-(R¹)-2H-pyrazol, and said first pyrazole derivative is        obtained in an amount that is greater than the amount of said        second pyrazole derivative;    -   said pyrazole derivative is a mixture of a first pyrazole        derivative and a second pyrazole derivative, wherein said first        pyrazole derivative has the nitrogen-member substitution pattern        in the pyrazole framework specified by 1-(R¹)-1H-pyrazol, said        second pyrazole derivative has the nitrogen-member substitution        pattern in the pyrazole framework specified by        2-(R¹)-2H-pyrazol, and said second pyrazole derivative is        obtained in an amount that is greater than the amount of said        first pyrazole derivative;    -   said pyrazole derivative is a mixture of a first pyrazole        derivative and a second pyrazole derivative, wherein said first        pyrazole derivative is        3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic        acid, said second pyrazole derivative is        3-[5-(3,4-dichloro-phenyl)-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-2-m-tolyl-propionic        acid, and said first pyrazole derivative is obtained in an        amount that is greater than the amount of said second pyrazole        derivative;    -   said pyrazole derivative is a mixture of a first pyrazole        derivative and a second pyrazole derivative, wherein said first        pyrazole derivative is        3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic        acid, said second pyrazole derivative is        3-[5-(3,4-dichloro-phenyl)-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-2-m-tolyl-propionic        acid, and said second pyrazole derivative is obtained in an        amount that is greater than the amount of said first pyrazole        derivative;    -   the Ar attached carbon is saturated and has the configuration    -   the Ar attached carbon is unsaturated and has the configuration    -   Ar, optionally substituted with R^(r) as described above, is        selected from the group GAr as described above, in more specific        embodiments Ar, optionally substituted with R^(r) as described        above, is selected from the group PGAr as described above, and        specific Ar are selected from the group SGAr as described above;    -   there are 0, 1, or 2 R^(r) substituents;    -   R^(r) is selected from the group GR^(r) as described above, and        in more specific embodiments R^(r) is selected from the group        PGR^(r) as described above;    -   R⁵ is selected from the group GR⁵ as described above, and in        more specific embodiments R⁵ is selected from the group PGR⁵ as        described above;    -   R⁴ is selected from the group consisting of —H, —F and —CH₃, and        in more specific embodiments R⁴ is H;    -   n is 0 or 1;    -   R¹, optionally substituted with R^(p) as described above, is        selected from the group GR¹ as described above, in more specific        embodiments R¹, optionally substituted with R^(p) as described        above, is selected from the group PGR¹ as described above, and        in even more specific embodiments R¹ is selected from the group        SGR¹ as described above;    -   R^(p) is selected from the group GR^(p) as described above, and        in more specific embodiments R^(p) is selected from the group        PGR^(p) as described above;    -   R², optionally substituted with R^(q) as described above, is        selected from the group GR² as described above, in more specific        embodiments R², optionally substituted with R^(q) as described        above, is selected from the group PGR² as described above, and        in even more specific embodiments R² is selected from the group        SGR² as described above;    -   R^(q) is selected from the group GR^(q) as described above, and        in more specific embodiments R^(q) is selected from the group        PGR^(q) as described above;    -   there are 0, 1, or 2 R^(q) substituents;    -   R³ is selected from the group consisting of —H, —F, Cl, Br and        —CH₃, and in more specific embodiments R³ is H;    -   the compound of formula (I) is        (S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic        acid;    -   the compound of formula (I) is (S)-sodium        3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate.

The assignments R³═H and n=1 in the structures displayed in Schemes P-Sare used as illustrations and they are not meant as limitations of theprocesses illustrated in Schemes P-S. As indicated above, it isunderstood that the teachings provided herein can be used together toapply the processes illustrated in Schemes P-S to the general range ofassignments for R³ and n as defined herein. Accordingly to thisdescription, P7 is one embodiment of P7′ and P8 is an embodiment of P8′,wherein P7′ and P8′ are also within the scope of the present invention,and they are represented by the following structures:

Furthermore, Q3 is one embodiment of Q3′, Q8 is one embodiment of Q8′(with the same structural representation as P8′), and S8 is anembodiment of S8′ (with the same structural representation as P8′),wherein Q3′, Q8′ and S8′ are also within the scope of the presentinvention, and they are represented by the following structures(structures for Q8′ and S8′ not given because they have the samestructural representation as P8′):

In addition, R5 is an embodiment of R5′, R6 is an embodiment of R6′, andR8 is an embodiment of R8′, wherein R5′, R6′, and R8′ are also withinthe scope of the present invention, and they are represented by thefollowing structures:

Choice of the more suitable of the Schemes disclosed herein, or of anycombination thereof, can be made in light of the teachings providedherein and the form of the desired final product (I). For example,embodiments of Scheme P are preferred for a compound with Ar and Hsubstituents at the stereogenic center, such as the title compound inExample 4. As an additional illustration, embodiments of Scheme Q aremore suitable for compounds with Ar and another substituent other than Hat the stereogenic center, such as the title compound in Example 76.

Processes according to the present invention include embodiments inwhich the regioselective and/or the stereoselective constraints areremoved. For example, regioselective reactions involving an inorganicbase, a substituted hydrazine, and an acetylenic ketone in a reactionmedium that are referred to above as involving a chiral acetylenicketone to form a chiral pyrazole derivative can also be performed insome embodiments with an acetylenic ketone that has no chirality to forma pyrazole derivative that has no chirality. For example, the titlecompound in Example 75 illustrates an embodiment of compound (I) inwhich chirality concerning a single sterogenic center is not relevantbecause it has no single stereogenic center. Furthermore, when a finalchiral compound is desired with no regioselectivity concerns,stereoselective synthetic steps taught herein can be combined with non-or low-regioselective synthetic steps, also taught herein.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. Inaddition, compounds of the invention may be modified by using protectinggroups; such compounds, precursors, or prodrugs are also within thescope of the invention. This may be achieved by means of conventionalprotecting groups, such as those described in “Protective Groups inOrganic Chemistry”, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W.Greene & P.G.M. Wuts, “Protective Groups in Organic Synthesis”, 3^(rd)ed., John Wiley & Sons, 1999. The protecting groups may be removed at aconvenient subsequent stage using methods known from the art.

Hydroxyl Protecting Groups

Protection for the hydroxyl group includes methyl ethers, substitutedmethyl ethers, substituted ethyl ethers, substituted benzyl ethers, andsilyl ethers.

Substituted Methyl Ethers

Examples of substituted methyl ethers include methyoxymethyl,methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

Substituted Ethyl Ethers

Examples of substituted ethyl ethers include 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, andbenzyl.

Substituted Benzyl Ethers

Examples of substituted benzyl ethers include p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl,3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl,5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(Imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9,9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.

Silyl Ethers

Examples of silyl ethers include trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,and t-butylmethoxyphenylsilyl.

Esters

In addition to ethers, a hydroxyl group may be protected as an ester.Examples of esters include formate, benzoylformate, acetate,chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate,4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate(mesitoate).

Carbonates

Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl,2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl,2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyldithiocarbonate.

Assisted Cleavage

Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethylbenzoate.

Miscellaneous Esters

Examples of miscellaneous esters include2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate,dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate.

Sulfonates

Examples of sulfonates include sulfate, methanesulfonate(mesylate),benzylsulfonate, and tosylate.

Protection for 1,2- and 1,3-Diols

Cyclic Acetals and Ketals

Examples of cyclic acetals and ketals include methylene, ethylidene,1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl)ethylidene,2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene,cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene,2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and2-nitrobenzylidene.

Cyclic Ortho Esters

Examples of cyclic ortho esters include methoxymethylene,ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene,1-ethoxyethylidine, 1,2-dimethoxyethylidene, α-methoxybenzylidene,1-(N,N-dimethylamino)ethylidene derivative,α-(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.

Silyl Derivatives

Examples of silyl derivatives include di-t-butylsilylene group, and1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative.

Amino Protecting Groups

Protection for the amino group includes carbamates, amides, and special—NH protective groups.

Examples of carbamates include methyl and ethyl carbamates, substitutedethyl carbamates, assisted cleavage carbamates, photolytic cleavagecarbamates, urea-type derivatives, and miscellaneous carbamates.

Carbamates

Examples of methyl and ethyl carbamates include methyl and ethyl,9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,9-(2,7-dibromo)fluorenylmethyl,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,and 4-methoxyphenacyl.

Substituted Ethyl

Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl,2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl,1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2′- and 4′-pyridyl)ethyl,2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl,allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl,N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl,p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl,4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.

Assisted Cleavage

Examples of assisted cleavage include 2-methylthioethyl,2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,[2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl,2-phosphonioethyl, 2-triphenylphosphonioisopropyl,1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl,p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and2-(trifluoromethyl)-6-chromonylmethyl.

Photolytic Cleavage

Examples of photolytic cleavage include m-nitrophenyl,3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, andphenyl(o-nitrophenyl)methyl.

Urea-Type Derivatives

Examples of urea-type derivatives include phenothiazinyl-(10)-carbonylderivative, N′-p-toluenesulfonylaminocarbonyl, andN′-phenylaminothiocarbonyl.

Miscellaneous Carbamates

Examples of miscellaneous carbamates include t-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl,isonicotinyl, p-(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-1-(3,5-dimethoxyphenyl)ethyl,1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1phenylethyl,1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and2,4,6-trimethylbenzyl.

Examples of amides include:

Amides

N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl,N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl,N-phenylbenzoyl.

Assisted Cleavage

N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl,(N′-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl,N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl,N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethioninederivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and4,5-diphenyl-3-oxazolin-2-one.

Cyclic Imide Derivatives

N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentaneadduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and1-substituted 3,5-dinitro-4-pyridonyl.

Special —NH Protective Groups

Examples of special NH protective groups include:

N-Alkyl and N-Aryl Amines

N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl,N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl),quaternary ammonium salts, N-benzyl, N-4-methoxybenzyl,N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl,N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, andN-2-picolylamine N′-oxide.

Imine Derivatives

N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene,N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, andN-(N′,N′-dimethylaminomethylene).

Protection for the Carbonyl Group

Acyclic Acetals and Ketals

Examples of acyclic acetals and ketals include dimethyl,bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and diacetyl.

Cyclic Acetals and Ketals

Examples of cyclic acetals and ketals include 1,3-dioxanes,5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane,5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes, 4-bromomethyl-1,3-dioxolane,4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane,4i2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane,O,O-phenylenedioxy and 1,5-dihydro-3H-2,4-benzodioxepin.

Acyclic Dithio Acetals and Ketals

Examples of acyclic dithio acetals and ketals include S,S′-dimethyl,S,S′-diethyl, S,S′-dipropyl, S,S′-dibutyl, S,S′-dipentyl, S,S′-diphenyl,S,S′-dibenzyl and S,S′-diacetyl.

Cyclic Dithio Acetals and Ketals

Examples of cyclic dithio acetals and ketals include 1,3-dithiane,1,3-dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin.

Acyclic Monothio Acetals and Ketals

Examples of acyclic monothio acetals and ketals includeO-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or -S-phenyl andO-methyl-S-2-(methylthio)ethyl.

Cyclic Monothio Acetals and Ketals

Examples of cyclic monothio acetals and ketals include 1,3-oxathiolanes.

Miscellaneous Derivatives

O-Substituted Cyanohydrins

Examples of O-substituted cyanohydrins include O-acetyl,O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.

Substituted Hydrazones

Examples of substituted hydrazones include N,N-dimethyl and2,4-dinitrophenyl.

Oxime Derivatives

Examples of oxime derivatives include O-methyl, O-benzyl andO-phenylthiomethyl.

Imines

Substituted Methylene Derivatives, Cyclic Derivatives

Examples of substituted methylene and cyclic derivatives includeoxazolidines, 1-methyl-2-(1′-hydroxyalkyl)imidazoles,N,N′-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles,diethylamine adducts, and methylaluminumbis(2,6-di-t-butyl-4-methylphenoxide)(MAD)complex.

Monoprotection of Dicarbonyl Compounds

Selective Protection of α-and β-Diketones

Examples of selective protection of α- and β-diketones include enamines,enol acetates, enol ethers, methyl, ethyl, i-butyl, piperidinyl,morpholinyl, 4-methyl-1,3-dioxolanyl, pyrrolidinyl, benzyl, S-butyl, andtrimethylsilyl.

Cyclic Ketals, Monothio and Dithio Ketals

Examples of cyclic ketals, monothio and dithio ketals includebismethylenedioxy derivatives and tetramethylbismethylenedioxyderivatives.

Protection for the Carboxyl Group

Esters

Substituted Methyl Esters

Examples of substituted methyl esters include 9-fluorenylmethyl,methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl,methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl,phenacyl, p-bromophenacyl, α-methylphenacyl, p-methoxyphenacyl,carboxamidomethyl, and N-phthalimidomethyl.

2-Substituted Ethyl Esters

Examples of 2-substituted ethyl esters include 2,2,2-trichloroethyl,

2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl,1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(p-toluenesulfonyl)ethyl,

2-(2′-pyridyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl,t-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl,4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, α-methylcinnamyl, phenyl,p-(methylmercapto)phenyl and benzyl.

Substituted Benzyl Esters

Examples of substituted benzyl esters include triphenylmethyl,diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl,2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl,p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl,2,6-dimethoxybenzyl, 4-methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl,4-picolyl and p-P-benzyl.

Silyl Esters

Examples of silyl esters include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl anddi-t-butylmethylsilyl.

Activated Esters

Examples of activated esters include thiols.

Miscellaneous Derivatives

Examples of miscellaneous derivatives include oxazoles,2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines,5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group andpentaaminocobalt(III) complex.

Stannyl Esters

Examples of stannyl esters include triethylstannyl andtri-n-butylstannyl.

Amides and Hydrazides

Amides

Examples of amides include N,N-dimethyl, pyrrolidinyl, piperidinyl,5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl,N-8-Nitro-1,2,3,4-tetrahydroquinolyl, and p-P-benzenesulfonamides.

Hydrazides

Examples of hydrazides include N-phenyl and N,N′-diisopropyl.

Compounds of the present invention may be used in pharmaceuticalcompositions to treat patients (humans and other mammals) with disordersinvolving the action of the CCK-1 receptor. As CCK-1 receptor modulatorsthe compounds may be divided into compounds, which are pure or partialagonists and compounds that are antagonists. Where the compound is aCCK-1 receptor antagonist, it may be used in the treatment of pain, drugdependence, anxiety, panic attack, schizophrenia, pancreatic disorder,secretory disorder, motility disorders, functional bowel disease,biliary colic, anorexia and cancer. Where the compound is a CCK-1receptor agonist, it may be used in the treatment of obesity,hypervigilance and gallstones.

The preferred route is oral administration, however compounds maybeadministered by intravenous infusion or topical administration. Oraldoses range from about 0.05 to 100 mg/kg, daily, taken in 1-4 separatedoses. Some compounds of the invention may be orally dosed in the rangeof about 0.05 to about 50 mg/kg daily, while others may be dosed at 0.05to about 20 mg/kg daily. Infusion doses can range from about 1.0 to1.0×10⁴ μg/kg/min of inhibitor, admixed with a pharmaceutical carrierover a period ranging from several minutes to several days. For topicaladministration compounds of the present invention I may be mixed with apharmaceutical carrier at a concentration of about 0.1 to about 10% ofdrug to vehicle.

The pharmaceutical compositions can be prepared using conventionalpharmaceutical excipients and compounding techniques. Oral dosage formsmay be elixers, syrups, capsules tablets and the like. Where the typicalsolid carrier is an inert substance such as lactose, starch, glucose,methylcellulose, magnesium sterate, dicalcium phosphate, mannitol andthe like; and typical liquid oral excipients include ethanol, glycerol,water and the like. All excipients may be mixed as needed withdisintegrants, diluents, granulating agents, lubricants, binders and thelike using conventional techniques known to those skilled in the art ofpreparing dosage forms. Parenteral dosage forms may be prepared usingwater or another sterile carrier.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value. Whenever a yield is given as apercentage, such yield refers to a mass of the entity for which theyield is given with respect to the maximum amount of the same entitythat could be obtained under the particular stoichiometric conditions.

EXAMPLES

NMR spectra were obtained on either a Bruker model DPX400 (400 MHz) orDPX500 (500 MHz) spectrometer. The format of the ¹H NMR data below is:chemical shift in ppm down field of the tetramethylsilane reference(multiplicity, coupling constant J in Hz, integration).

Mass spectra were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in either positive or negative mode asindicated. The “mass calculated” for a molecular formula is themonoisotopic mass of the compound.

Protocol for Reversed-Phase HPLC (Method A):

-   Manufactured by Agilent HPLC 1100;-   Column: Zorbax Eclipse XDB-C8, 5 μm, 4.6×150 mm;-   Flow rate: 0.75 mL/min; λ=220 & 254 nm;-   Gradient (Acetonitrile/Water):-   1) 0.0 min 1% Acetonitrile-   2) 8.0 min 99% Acetonitrile-   3) 12.0 min 99% Acetonitrile    Protocol for Reversed-Phase HPLC (Method B):-   Manufactured by Agilent HPLC 1100;-   Column: Xterra™, RP18, 3.5 μm, 4.6×50 mm;-   Flow rate: 1.5 mL/min; λ=220 & 254 nm;-   Gradient (Acetonitrile/Water):-   1) 0.0 min 85% Acetonitrile-   2) 3.5 min 1.0% Acetonitrile-   3) 5 min 1.0% AcetonitrHe    Protocol for Chiral HPLC (Method C):-   Manufactured by Agilent HPLC 1100;-   Chiral Column: Chiralpak AD, 4.6×250 mm;-   Column Manufacturer: Chiral Technologies Inc.;-   Mobile Phase: 85:15 Ethanol/Hexane with 0.1% TFA;-   Flow Rate: 0.75 mL/min; λ=220 & 254 nm    Protocol for Semi-Preparation. Chiral HPLC (Method D):-   Manufactured by Agilent HPLC 1100;-   Chiral Column: Chiralpak AD, 20×250 mm;-   Column Manufacturer: Chiral Technologies Inc.;-   Mobile Phase: 85:15 Ethanol/Hexane with 0.1% TFA;-   Flow Rate: 7 mL/min; λ=220 & 254 nm    Reversed-Phase HPLC (Method E):-   Column: Zorbax Eclipse XDB-C8, 5 μm, 4.6×150 mm;-   Flow rate: 0.75 mL/min; λ=220 & 254 nm;-   Gradient (Acetonitrile/Water):-   1) 8.0 min 1%-99% Acetonitrile-   2) 10.0 min 99% Acetonitrile    Chiral HPLC (Method F):-   Column: Chiralcel AD 0.46×25 cm;-   Mobile Phase: 85:15 Ethanol/Hexane with 0.07% TFA;-   Flow rate: 1 mL/min; λ=220 & 254 nm    Reversed-Phase HPLC (Method G):-   Column: XTerra Prep MS C18, 5 μm, 19×50 mm;-   Mobile Phase: Acetonitrile/Water with 0.1% TFA;-   Flow rate: 25 mL/min; λ=220 & 254 nm;-   Gradient:-   1) 0.0 min 15% Acetonitrile-   2) 13.0 min 99% Acetonitrile-   3) 15.0 min 99% Acetonitrile    Protocol for Reversed-Phase HPLC (Method H):-   Manufactured by Agilent HPLC 1100;-   Column: Chromolith SpeedROD, 4.6×50 mm;-   Mobile Phase: Acetonitrile/Water with 0.1% TFA;-   Flow rate: 5 mL/min; λ=220 & 254 nm;-   Gradient (Acetonitrile/Water):-   1) 0.0 min 85% Acetonitrile-   2) 2.0 min 1.0% Acetonitrile-   3) 2.5 min 1.0% Acetonitrile    Protocol for Reversed-Phase HPLC (Method I):-   Manufactured by Agilent HPLC 1100;-   Column: Xterra™, RP18, 3.5 μm, 4.6×50 mm;-   Mobile Phase: Acetonitrile/Water with 10 mM NH₄OH;-   Flow rate: 1 mL/min; λ=220 & 254 nm;-   Gradient (Acetonitrile/Water):-   1) 0.0 min 1% Acetonitrile-   2) 7.0 min 99% Acetonitrile-   3) 10.0 min 99% Acetonitrile    HPLC Method J; (Chiral)-   Chiralcel AD 0.46 cm×25 cm column-   Flow rate: 1 mL/min; λ=220 nm & 254 nm-   Solvent: 60/40 EtOH/Hexane-   Gradient conditions: Isocratic-   Reported retention times (R_(t)) are in minutes.

Example 1

(S)-Sodium;3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate

A. Lithium 4-(3,4-dichlorophenyl)-4-hydroxy-2-oxo-but-3-enoic acid ethylester. In a dried 1-L round-bottomed flask, lithiumbis(trimethylsilyl)amide in tetrahydrofuran (THF) (265 mL, 0.265 mol)was concentrated under reduced pressure to a solid using a rotaryevaporator at 25-30° C. Anhydrous diethyl ether (200 mL) was added andthis stirred suspension of LHMDS in diethyl ether was cooled to −78° C.under N₂. 3,4-Dichloracetophenone (50.0 g, 0.265 mol) in diethyl ether(200 mL) was slowly added to the reaction mixture over 15 min. Themixture was allowed to stir for 60 min, and diethyl oxalate (36.0 mL,0.265 mol) in diethyl ether (75 mL) was then added over 20 min. After 90min, the mixture was allowed to warm to room temperature (rt) andstirred overnight. The light yellow solids were filtered, washed withdiethyl ether and dried in vacuum to afford 78.4 g of lithium4-(3,4-dichlorophenyl)-4-hydroxy-2-oxo-but-3-enoic acid ethyl ester as awhite solid. This material was used in the next step without furtherpurification.

B. 5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole-3-carboxylicacid ethyl ester. A stirred suspension of lithium4-(3,4-dichlorophenyl)--4-hydroxy-2-oxo-but-3-enoic acid ethyl ester(90.7 g, 0.307 mol) and 4-methoxyphenyl hydrazine hydrochloride (54.0 g,0.309 mol) in EtOH (600 mL) was heated to 55° C. for 5 h then stirred atrt overnight. HPLC analysis showed a 4:1 mixture of5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole-3-carboxylicacid ethyl ester and5-(3,4-dichloro-phenyl)-2-(4-methoxy-phenyl)-2H-pyrazole-3-carboxylicacid ethyl ester. The precipitated solids were filtered and washed withEtOH. The solids were recrystallized with 1:1 CH₃CN/MeOH to recover 9.0g of minor product5-(3,4-dichloro-phenyl)-2-(4-methoxy-phenyl)-2H-pyrazole-3-carboxylicacid ethyl ester. Crystallization was repeated several times to recover71.0 9 of major product5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole-3-carboxylicacid ethyl ester. The crude filtrate was purified by columnchromatography (silica gel, 4:1 hexane/ethyl acetate (EtOAc)) to recoveranother 17.6 g of5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole-3-carboxylicacid ethyl ester for a total combined yield of 74%. HPLC: R_(t)=10.57(Method E). MS (ES+): mass calculated for C₁₉H₁₆Cl₂N₂O₃, 391.25; m/zfound 392.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.37 (d, J=2.0 Hz,1H), 7.35(d, J=8.4 Hz, 1H), 7.26-7.22 (m, 2H), 7.04 (s, 1H), 6.97 (dd, J=8.0, 1.0Hz, 1H), 6.95-6.88 (m, 2H), 4.45 (q, J=7.1 Hz, 2H), 3.84 (s, 3H), 1.42(q, J=7.1 Hz, 3H).

C.[5-(3,4-Dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-methanol.To a stirred solution of5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole-3-carboxylicacid ethyl ester (55.7 g, 0.140 mol) in THF (150 mL) at −78° C. under N₂was slowly added a 1.0 M solution of diisobutylaluminum hydride(DIBAL-H) (350 mL, 0.35 mol) over 45 min. The solution was allowed tostir for 20 min then warmed to rt over 90 min. The mixture was thencooled to 0° C., and a saturated solution of potassium sodium tartrate(300 mL) and EtOAc (400 mL) was added. The slurry mixture was stirredovernight whereupon both layers became clear. The organic layer wasextracted with EtOAc (2×75 mL), dried with Na₂SO₄, filtered andconcentrated. The crude product was dried under vacuum to recover 46.8 g(96%) of the title compound. This was used in the next step withoutfurther purification. HPLC: R_(t)=9.16 (Method E). MS (ES+): masscalculated for C₁₇H₁₄Cl₂N₂O₂, 349.21; m/z found 371.1 [M+Na]⁺. ¹H NMR(400 MHz, CDCl₃): 7.39 (d, J=2.1 Hz, 1H), 7.34 (d, J=3.6 Hz, 1H),7.20-7.09 (m, 2H), 6.97 (dd, J=8.36, 2.1 Hz,1H), 6.91-6.79 (m, 2H), 6.43(s, 1H), 4.69 (s, 2H), 3.74 (s, 3H).

D. Methanesulfonic acid5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-ylmethyl ester.To a stirred solution of[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-methanol(7.2 g, 0.021 mol) in THF (125 mL) and triethylamine (TEA) (4.6 mL,0.033 mol) was added methanesulfonyl chloride (2.5 mL, 0.031 mol). Thereaction mixture was stirred at 45° C. for 4 h. The reaction mixture wascooled to rt, quenched with H₂O (75 mL) then washed with EtOAc (3×50mL). The organic layer was dried over Na₂SO₄, filtered and concentratedto oil. This crude pyrazole mesylate was used in the next step withoutfurther purification. HPLC: R_(t)=10.03 (Method E). MS (ES+): masscalculated for C₁₈H₁₈Cl₂N₂O₄S, 427.30; m/z found 428.1 [M+H]⁺.

E. 5-(3,4-Dichloro-phenyl)-3-iodomethyl-1-(4-methoxyphenyl)-1H-pyrazole.A stirred solution of methanesulfonic acid5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-ylmethyl ester(8.80 g, 0.0206 mol) and NaI (4.64 g, 0.0309 mol) in acetone (175 mL)was refluxed for 90 min. The thick reaction slurry was cooled to rt,quenched with H₂O (200 mL) and extracted with EtOAc (3×75 mL). Theorganic layer was dried with Na₂SO₄, filtered and concentrated to a darkoil. The crude oil was purified by column chromatography (silica gel,85:15 hexane/EtOAc) to obtain 9.15 g (97%) of the title compound aftertwo steps. HPLC: R_(t)=11.03 (Method E). MS (ES+): mass calculated forC₁₇H₁₃Cl₂IN₂O, 459.10; m/z found 460.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.37 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H),6.95 (dd, J=6.3, 2.0 Hz, 1H), 6.88 (d, J=9.1 Hz, 2H), 6.55 (s, 1H), 4.47(s, 2H), 3.83 (s, 3H).

F.(3aS,8aR)-3-(2-m-Tolyl-acetyl)-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one.To a stirred solution of m-tolylacetic acid (8.57 g, 0.0571 mol),2-chloro-1-methylpyridinium iodide (19.0 g, 0.0744 mol) and(3aS-cis)-(−)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]-oxazol-2-one (10.0g, 0.0571 mol) in CH₂Cl₂ (130 mL) were added TEA (18.0 mL, 0.129 mol)and 4-dimethylaminopyridine (DMAP, 1.39 g, 0.0114 mol) at 0° C. Thereaction mixture was stirred at rt for 3 h then treated with hexane (130mL). The resulting slurry was passed through a pad of silica gel,eluting with 3:2 EtOAc/hexane. The filtrate was concentrated to an oiland recrystallized in hot hexane to recover 13 g (74%) of the titlecompound as a white solid. HPLC: R_(t)=9.85 (Method E). MS (ES+): masscalculated for C₁₉H₁₇NO₃, 307.36; m/z found 330.2 [M+Na]⁺. ¹H NMR (400MHz, CDCl₃): 7.65 (d, J=7.6 Hz, 1H), 7.08-7.37 (m, 7H), 5.95 (d, J=6.8Hz, 1H), 5.27-5.31 (m, 1H), 4.26 (dd, J=15.9, 39.1 Hz, 2H), 3.40 (d,J=3.5 Hz, 2H), 2.34 (s, 3H).

G.(2S,3aS,8aR)-3-{3-[5-(3,4-Dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionyl}-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one.To a stirred solution of(3aS,8aR)-3-(2-m-tolyl-acetyl)-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one(product of Step F., 12 g, 0.039 mol) in THF (100 mL) was added 1.0 Msodium 1,1,1,3,3,3-hexamethyldisilazane (NaHMDS) (41 mL, 0.041 mol) inTHF at −78° C. The mixture was stirred for 45 min at −78° C. thentreated with5-(3,4-dichloro-phenyl)-3-iodomethyl-1-(4-methoxy-phenyl)-1l-H-pyrazole(product of Step E., 18.4 g, 0.0405 mol) in THF (100 mL). The reactionmixture was allowed to warm to rt overnight and then was quenched withH₂O (100 mL) and concentrated to half the volume. The aqueous layer waswashed with EtOAc (3×75 mL). The extracted organic layer was washed withsaturated NaCl, dried over Na₂SO₄, filtered and concentrated to an oil.The crude oil was purified by flash column chromatography (silica gel,7:3 hexane/EtOAc) to obtain 20.7 g of the title compound (83%) as whitefoam. HPLC: R_(t)=11.38 (Method E). MS (ES+): mass calculated forC₃₆H₂₉Cl₂N₃O₄, 638.55; m/z found 660.3 [M+Na]⁺. ¹H NMR (400 MHz, CDCl₃):7.52 (d, J=7.6 Hz, 1H), 7.11-7.35 (m, 8H), 6.93-6.99 (m, 3H), 6.74-6.82(m, 3H), 6.20 (s, 1H), 5.89 (d, J=6.8 Hz, 1H), 5.58 (q, J=6.1, 4.5 Hz,1H), 5.11-5.15 (m, 1H), 3.8 (s, 3H), 3.72 (dd, J=10.6, 4.1 Hz, 1H), 3.33(br, s, 2H), 3.07 (dd, J=9.8, 4.8 Hz, 1H), 2.37 (s, 3H).

H.(S)-3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid. To a stirred solution of(2S,3aS,8aR)-3-{3-[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionyl}-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one(20.7 g, 0.0323 mol) in THF (230 mL) and H₂O (45 mL) at 0° C. was added30% H₂O₂ (15.0 mL, 0.147 mol) followed by LiOH hydrate (2.75 g, 0.0655mol) in H₂O (15 mL). The reaction mixture was allowed to warm to rt andwas stirred for 90 min. The mixture was cooled to 0° C. and thenquenched with 1.5 N Na₂SO₃ (20 mL) maintaining pH 9-10. The mixture wasconcentrated to ¼ volume, then treated with H₂O (200 mL) and acidifiedto pH 1-2 using 3 N HCl. The aqueous layer was washed with EtOAc (3×100mL). The combined organic layers were dried with Na₂SO₄, filtered andconcentrated to ¼ volume. Solid crystals that developed overnight werefiltered and washed with cold 1:1 hexane/EtOAc. The chiral auxiliary wasrecovered in 66% yield (3.72 g). The filtrate was purified by flashchromatography (7:3 hexane/EtOAc with 0.3% MeOH) to afford 12.7 g(81.5%) of(S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid as orange oil. HPLC: R_(t)=10.44 (Method E). MS (ES+): masscalculated for C₂₆H₂₂Cl₂N₃, 481.37; m/z found 503.2 [M+Na]⁺. ¹H NMR (400MHz, CDCl₃): 7.12-7.31 (m, 9H), 6.90 (dd, J=6.3, 2.0 Hz, 1H), 6.86 (d,J=9.1 Hz, 2H), 6.21 (s, 1H), 4.07-4.15 (m, 1H), 3.82 (s, 3H), 3.53 (dd,J=9.3, 5.3 Hz, 1H), 3.10 (dd, J=9.1, 5.8 Hz, 1H), 2.35 (s, 3H).

I. (S)-Sodium;3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate.To a stirred solution of(S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid (12.7 g, 0.0264 mol) in THF (125 mL) was added aqueous NaOH (1.05g, 0.0264 mol in H₂O, 10 mL) at 0° C. The mixture was stirred for 30 minat 0° C. then concentrated to an oil under reduced pressure using arotary evaporator (25-30 ° C.). The oil was diluted in THF (150 mL),chilled in an ice bath and CH₃CN (50 mL) was added where upon aprecipitate developed. The suspension was stirred for 2 h, filtered andthen washed with CH₃CN to afford 10.9 g (67%) of the title compound as awhite solid. HPLC: R_(t)=7.10 (Method F). HRMS: exact mass of [M+H]⁺calculated for C₂₆H₂₂Cl₂N₂O₃, 481.1086; m/z found, 481.1079. M.P.295.5-297.5 ° C. Anal. Calcd for C₂₅H₁₈Cl₂N₂NaO₃: C, 61.49; H, 3.72; N,5.74 Found: C, 61.98; H, 4.14; N, 5.43. Optical rotation {α]²⁰ ₅₈₉+58.8°(c=0.1, EtOH). ¹H NMR (400 MHz, D₂O); 6.90-6.93 (m, 2H), 6.77 (t, J=7.3Hz, 1H), 6.61 (d, J=9.1 Hz, 2H), 6.53 (d, J=7.3 Hz, 1H), 6.38 (t, J=8.6Hz, 4H), 6.12 (d, J=8.1 Hz, 1H), 5.46 (s, 1H), 3.55-3.63 (m, 1H), 3.22(s, 3H), 3.06-3.18 (m, 2H), 1.81 (s, 3H). ¹³C NMR (100 MHz. DMSO-d₆):175.3, 157.9, 152.5, 143.6, 139.2, 135.7, 132.1, 130.7, 130.5, 130.1,130.0, 129.2, 128.0, 127.7, 126.9, 126.1, 125.4, 124.5, 113.7,107.0,.54.9, 54.5, 32.6, 20.6 ppm.

Method 1

Synthesis of 3-Bromomethyl-1,5-diaryl-1H-pyrazoles (Pyrazole Bromides)

such as:

3-Bromomethyl-1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazole

A solution of phosphorus tribromide (9.31 g, 34.5 mmol) in CH₂Cl₂ (186mL) was added drop-wise to a stirred solution of[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-methanol (7.80 g, 26.5mmol; prepared analogously to the procedure described in Step C ofExample 1) in 50 mL CH₂Cl₂ at 0° C. The reaction mixture was stirred foran additional 18 h at rt, and then the mixture was neutralized byaddition of 40% NaOH with cooling in an ice bath. The organic layer wasseparated and dried over Na₂SO₄, and solvent was removed under reducedpressure. The residue was purified by silica gel chromatography (CH₂Cl₂)yielding 8.09 g (86%) of3-bromomethyl-1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazole. HPLC:R_(t)=10.38. (Method A). MS (ES+): mass calculated for C₁₈H₁₇BrN₂O,356.05; m/z found 357.5 {M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.42 (s, 4H),7.39-7.34 (m, 2H), 7.02-6.98 (m, 2H), 6.69 (s, 2H), 4.73 (s, 2H), 3.97(s, 1H), 2.49 (s, 3H).

Method 2

General Method for the Synthesis of3-(1,5-Diaryl-1H-pyrazol-3-yl)-2-aryl-propionic Acids (A9)

Scheme A. In each of eight 10-mL test tubes, 60% NaH in mineral oil (18mg, 0.45 mmol) was suspended in 5 mL of N,N-dimethylformamide (DMF) at0° C. under N₂. Then, to each test tube, a unique phenyl-acetic acidester (A10) was added, and the reaction mixtures were stirred for 1 h.Equal portions of the first such mixture were then loaded into the sixwells of the first row of a 48-well Robbins block under N₂, and equalportions of the next mixture were loaded into the six wells of thesecond row, and so on, until all eight reaction mixtures had beenapportioned, and all forty-eight wells had been loaded. Then, 0.15 mmolof one of six different pyrazole bromides (A7, prepared analogously tothe procedure described in Method 1) in 0.5 mL DMF was loaded into eachof eight wells of the first of six orthogonal columns of the block, and0.15 mmol of a second pyrazole bromide in 0.5 mL DMF was loaded intoeach of eight wells of the second column of the block, and so on,yielding a matrix of forty-eight unique reaction mixtures. After theblock was shaken for 18 h at rt, 0.3 mL of 2 M aqueous LiOH was added toeach well, and the block was shaken an additional 18 h at rt. Thesolutions were drained into the 48 wells of a Beckman microtitercollection plate, and the solvent was removed under reduced pressure.Each residue was dissolved in 1.5 mL of DMF and purified on a Gilson 215prep-HPLC system (Method G; recoveries of 12-34 mg for the products,16-44% yield, isolated as TFA salts).

Example 2

3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=10.46 (MethodA), R_(t)=4.81, 7.95 (Method C). MS (ES+): mass calculated forC₂₆H₂₂Cl₂N₂O₃, 480.10; m/z found 481.1 {M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.31-7.28 (m, 2H), 7.22 (d, J=7.6 Hz, 1H), 7.21-7.18 (m, 2H), 7.14-7.08(m, 3H), 6.89 (dd, J=5.3, 2.0 Hz, 1H), 6.85 (d, J=8.5 Hz, 2H), 6.22 (s,1H), 4.13-4.07 (m, 1H), 3.82 (s, 3H), 3.52 (dd, J=14.4, 9.1, Hz, 1H),3.12 (dd, J=10.1, 5.3 Hz, 1H), 2.01 (s, 3H).

Example 3

(R)-3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The racemate (Example 2) was prepared,by Method 2, and the titlecompound was separated by semi-preparative HPLC (Method D). HPLC:R_(t)=10.44 (Method A), R_(t)=4.81 (Method C). MS (ES+): mass calculatedfor C₂₆H₂₂Cl₂N₂O₃, 480.10; m/z found 481.1 [M+H]⁺. Optical rotation{α]²⁰ ₅₈₉−91.0 (c=0.1, EtOH). ¹H NMR (400 MHz, CDCl₃): 7.31 (t, J=2.21H), 7.29 (s, 1H), 7.22 (d, J=7.4 Hz, 1H), 7.20-7.16 (m, 2H), 7.16-7.09(m, 3H), 6.89 (dd, J=8.4, 2.1 Hz, 1H), 6.87-6.84 (m, 2H), 6.22 (s, 1H),4.10 (dd, J=9.2, 6.1 Hz, 1H), 3.83 (s, 3H), 3.51 (dd, J=15.0, 9.7 Hz,1H), 3.11 (dd, J=15.2, 5.2 Hz, 1H), 2.34 (s, 3H).

Example 4

(S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The racemate (Example 2) was prepared by Method 2, and the titlecompound was separated by semi-preparative HPLC (Method D). HPLC:R_(t)=10.44 (Method A), R_(t)=7.95 (Method C). MS (ES+): mass calculatedfor C₂₆H₂₂Cl₂N₂O₃, 480.10; m/z found 481.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.31 (t, J=2.2 1H), 7.29 (s, 1H), 7.22 (d, J=7.4 Hz, 1H),7.20-7.16 (m, 2H), 7.16-7.09 (m, 3H), 6.89 (dd, J=8.4, 2.1 Hz, 1H),6.87-6.84 (m, 2H), 6.22 (s, 1H), 4.10 (dd, J=9.2, 6.1 Hz, 1H), 3.83 (s,3H), 3.51 (dd, J=15.0, 9.7 Hz, 1H), 3.11 (dd, J=15.2, 5.2 Hz, 1H), 2.34(s, 3H).

Example 5

2-(4-Methoxy-phenyl)-3-[-1-(4-methoxyl-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=9.51 (MethodA). MS (ES+): mass calculated for C₂₇H₂₆N₂O₄, 442.21; m/z found 443.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.30 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.5Hz, 2H), 7.07-7.04 (m, 4H), 6.86 (d, J=8.5 Hz, 2H), 6.81 (d, J=8.5 Hz,2H), 6.17 (s, 1H), 4.01 (dd, J=9.4, 5.3 Hz, 1H), 3.79 (s, 6H), 3.50 (dd,J=15.0, 9.1 Hz, 1H), 3.10 (dd, J=15.0, 6.0 Hz, 1H), 2.32 (s, 3H).

Example 6

2-(3-Methoxy-phenyl)-3-[1-(4-methoxy-phenyl)-5-p-toly-1H-pyrazol-3-yl]-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=9.58 (MethodA). MS (ES+): mass calculated for C₂₇H₂₆N₂O₄, 442.19; m/z found 443.2{M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.27-7.22 (m, 2H), 7.17-7.12 (m, 2H),7.08-7.02 (m, 3H), 6.99-6.92 (m, 2H), 6.84-6.79 (m, 2H), 6.18 (s, 1H),4.01 (dd, J=9.4, 5.3 Hz, 1H), 3.80 (s, 6H), 3.50 (dd, J=15.0, 9.1 Hz,1H), 3.10 (dd, J=15.0, 6.0 Hz, 1H), 2.32 (s, 3H).

Example 7

2-(3-Chloro-phenyl)-3-[1-(4-methoxy-phenyl)-5-p-toly-1H-pyrazol-3-yl]-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=9.99 (MethodA). MS (ES+): mass calculated for C₂₇H₂₅ClN₂O₃, 446.16; m/z found 447.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.38-7.36 (m, 2H), 7.27-7.25 (m, 2H),7.16-7.11 (m, 2H), 7.08-7.02 (m, 4H), 6.84-6.78 (m, 2H), 6.18 (s, 1H),4.13-4.07 (m, 1H), 3.08 (s, 3H), 3.51 (dd, J=14.9, 9.0 Hz, 1H), 3.10(dd, J=15.0, 6.0 Hz, 1H), 2.32 (s, 3H).

Example 8

3-[1-(4-Methoxy-phenyl)-5-p-toly-1H-pyrazol-3-yl]-2-p-tolyl-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=9.89 (MethodA). MS (ES+): mass calculated for C₂₇H₂₆N₂O₃, 426.19; m/z found 427.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.28-7.25 (m, 2H), 7.18-7.12 (m, 4H),7.08-7.02 (m, 4H), 6.83-6.79 (m, 2H), 6.19 (s, 1H), 4.13-4.05 (m, 1H),3.80 (s, 3H), 3.50 (dd, J=15.0, 9.1 Hz, 1H), 3.10 (dd, J=15.0, 6.0 Hz,1H), 2.32 (s, 6H).

Example 9

2-(4-Chloro-phenyl)-3-[1-(4-methoxy-phenyl)-5-p-toly-1H-pyrazol-3-yl]-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=10.00 (MethodA). MS (ES+): mass calculated for C₂₇H₂₃ClN₂O₃, 446.14; m/z found 447.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.37 (br, s, 4H), 7.14-7.11 (m, 2H),7.09-7.01 (m, 4H), 6.83-6.80 (m, 2H), 6.16 (s, 1H), 4.15-4.11 (m, 1H),3.80 (s, 3H), 3.50 (dd, J=15.0, 9.1 Hz, 1H), 3.10 (dd, J=15.0, 6.0 Hz,1H), 2.32 (s, 3H).

Example 10

3-[5-(2-Chloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=9.87 (MethodA). MS (ES+): mass calculated for C₂₉H₂₃ClN₂O₃, 482.14; m/z found 483.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.14 (d, J=8.3 Hz, 1H), 7.80 (d, J=7.8Hz, 2H), 7.62-7.59 (m, 1H), 7.52-7.44 (m, 3H), 7.33-7.29 (m, 1H),7.26-7.22 (m, 1H), 7.16-7.12 (m, 1H), 7.05-7.01 (m, 2H), 7.00-6.97 (m,1H), 6.75-6.71 (m, 2H), 6.08 (s, 1H), 4.98 (dd, J=8.6, 6.6 Hz, 1H), 3.77(dd, J=19.2, 4.2 Hz, 1H), 3.75 (s, 3H), 3.34 (dd, J=14.6, 6.57 Hz, 1H).

Example 11

2-(3-Chloro-phenyl)-3-[5-(2-chloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=9.78 (MethodA). MS (ES+): mass calculated for C₂₅H₂₀Cl₂N₂O₃, 466.09; m/z found 467.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.37-7.34 (m, 2H), 7.29-7.24 (m, 4H),7.19-7.07 (m, 2H), 7.14 (dd, J=8.0, 2.0 Hz, 2H), 6.77-6.73 (m, 2H), 6.16(s, 1H), 4.14 (dd, J=8.3, 1.7 Hz, 1H), 3.76 (s, 3H), 3.53 (dd, J=14.7,8.0 Hz, 1H), 3.17 (dd, J=15.2, 8.0 Hz, 1H).

Example 12

3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-phenyl-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=9.78 (MethodA). MS (ES+): mass calculated for C₂₅H₂₀Cl₂N₂O₃, 466.09; m/z found 467.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.37-7.34 (m, 2H), 7.29-7.24 (m, 4H),7.19-7.07 (m, 2H), 7.14 (dd, J=8.0, 2.0 Hz, 2H), 6.77-6.73 (m, 2H), 6.16(s, 1H), 4.14 (dd, J=8.3, 1.7 Hz, 1H), 3.76 (s, 3H), 3.53 (dd, J=14.7,8.0 Hz, 1H), 3.17 (dd, J=15.2, 8.0 Hz, 1H).

Example 13

3-[5-Benzo[1,3]dioxol-5-yl-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-(3-methoxy-phenyl)-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=9.03 (MethodA). MS (ES+): mass calculated for C₂₇H₂₄N₂O₆, 472.16; m/z found 473.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.10-7.01 (m, 2H), 6.97-6.93 (m, 2H),6.77 (d, J=8.3 Hz, 1H), 6.73 (t, J=2.2 Hz, 1H), 6.62 (d, J=8.5 Hz, 2H),6.51 (d, J=8.8 Hz, 1H), 6.44 (dd, J=8.0 Hz, 1.7 Hz, 1H), 6.39 (d, J=1.2Hz, 1H), 5.94 (s, 1H), 5.75 (s, 2H), 3.91 (dd, J=9.3, 5.8 Hz, 1H), 3.60(s, 3H), 3.59 (s, 3H), 3.31 (dd, J=14.6, 9.3 Hz, 1H), 2.93 (dd, J=13.6,6.5 Hz, 1H).

Example 14

2-Benzofuran-3-yl-3-[1,5-bis-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=9.28 (MethodA). MS (ES+): mass calculated for C₂₈H₂₄N₂O₅, 468.17; m/z found 469.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.45 (d, J=2.0 Hz, 1H), 7.29-7.25 (m,1H), 7.12-7.09 (m, 3H), 6.96-6.93 (m, 2H), 6.86-6.82 (m, 2H), 6.77-6.75(m, 1H), 6.64-6.58 (m, 4H), 5.88 (s, 1H), 4.29 (dd, J=8.8, 6.0 Hz, 1H),3.63 (s, 3H), 3.62 (s, 3H), 3.50 (dd, J=14.4, 9.3 Hz, 1H), 3.05 (dd,J=14.9, 6.2 Hz, 1H).

Example 15

3-[1-(4-Methoxy-phenyl)-5-phenyl-1H-pyrazol-3-yl]-2-naphthalen-2-yl-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=9.79 (MethodA). MS (ES+): mass calculated for C₂₉H₂₄N₂O₃, 448.18; m/z found 449.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.86-7.79 (m, 4H), 7.55-7.51 (m, 1H),7.50-7.46 (m, 2H), 7.29-7.22 (m, 2H), 7.14-7.16 (m, 4H), 6.86-6.77 (m,2H), 6.26 (s, 1H), 4.33 (dd, J=8.8, 6.3 Hz, 1H), 3.78 (s, 3H), 3.60 (dd,J=15.0, 8.8 Hz, 1H), 3.29 (dd, J=14.6, 6.0 Hz, 1H).

Example 16

3-[1-(4-Methoxy-phenyl)-5-(4-phenoxy-phenyl)-1H-pyrazol-3-yl]-2-(3-nitro-phenyl)-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=3.47 (MethodB). MS (ES+): mass calculated for C₃₁H₂₅N₃O₆, 535.17; m/z found536.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.23 (t, J=1.5 Hz, 1H), 8.18-8.15(m, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.39-7.34 (m,2H), 7.17-7.13 (m, 3H), 7.10-7.06 (m, 2H), 7.04-7.00 (m, 2H), 6.90-6.84(m, 4H), 6.23 (s, 1H), 4.32 (dd, J=8.3, 6.5 Hz, 1H), 3.82 (s, 3H), 3.61(dd, J=15.2, 8.6 Hz, 1H), 3.24 (dd, J=15.2, 6.3 Hz, 1H).

Example 17

2-Benzo[1,3]dioxol-4-yl-3[5-benzo[1,3]dioxol-5-yl-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=2.91 (MethodB). MS (ES+): mass calculated for C₂₇H₂₂N₂O₇, 486.14; m/z found 487.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.18-7.14 (m, 2H), 6.89 (d, J=1.7 Hz,1H), 6.86-6.83 (m, 2H), 6.81 (d, J=1.5 Hz, 1H), 6.74 (dd, J=19.2, 7.8Hz, 2H), 6.65 (dd, J=7.83, 1.7 Hz, 1H), 6.59 (d, J=1.7 Hz, 1H), 6.17 (s,1H), 5.95 (s, 4H), 4.06 (dd, J=9.1, 6.1 Hz, 1H), 3.81 (s, 3H), 3.48 (dd,J=15.2, 8.8 Hz, 1H), 3.10 (dd, J=15.9, 7.0 Hz, 1H).

Example 18

3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-(2,3-difluoro-phenyl)-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=3.62 (MethodB). MS (ES+): mass calculated for C₂₅H₁₈Cl₂F₂N₂O₃, 502.07; m/z found503.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.31 (d, J=8.3 Hz, 1H), 7.29 (d,J=2.0 Hz, 1H), 7.16-7.05 (m, 5H), 6.91-6.84 (m, 3H), 6.25 (s, 1H), 4.46(dd, J=8.0, 7.0 Hz, 1H), 3.82 (s, 3H), 3.57 (dd, J=15.1, 8.3 Hz, 1H),3.18 (dd, J=14.6, 7.0 Hz, 1H).

Example 19

3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-(2-trifluoromethyl-phenyl)-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=3.50 (MethodB). MS (ES+): mass calculated for C₂₆H₁₉Cl₂F₃N₂O₃, 534.07; m/z found535.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.71-7.66 (m, 2H), 7.57 (t, J=8.3Hz, 1H), 7.41 (t, J=7.3 Hz, 1H), 7.31 (s, 1H), 7.29 (d, J=1.5 Hz, 1H),7.14-7.10 (m, 2H), 6.89 (dd, J=8.34, 2.2 Hz, 1H), 6.87-6.82 (m, 2H),6.20 (s, 1H), 4.56 (d=9.3, 5.5 Hz, 1H), 3.81 (s, 3H), 3.55 (dd, J=15.6,8.5 Hz, 1H), 3.13 (dd, J=15.16, 6.0 Hz, 1H).

Example 20

3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-(3-ethoxy-phenyl)-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=5.34 (MethodB). MS (ES+): mass calculated for C₂₇H₂₄Cl₂N₂O₄, 510.11; m/z found 511.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.32 (s, 1H), 7.29 (d, J=2.2 Hz, 1H),7.27-7.23 (m, 2H), 7.15-7.12 (m, 2H), 6.95-6.82 (m, 5H), 6.24 (s, 1H),4.08 (dd, J=9.3, 5.5 Hz, 1H), 4.07 (q, J=13.8, 7.0 Hz, 2H), 3.82 (s,3H), 3.52 (dd, J=15.6, 9.0 Hz, 1H), 3.14 (dd, J=15.4, 5.8 Hz, 1H), 1.40(t, J=6.8 Hz, 3H).

Example 21

3-[1-(3,4-Dichloro-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-(2-fluoro-3-trifluoromethyl-phenyl)-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=3.78 (MethodB). MS (ES+): mass calculated for C₂₆H₁₈Cl₂F₄N₂O₃, 536.07; m/z found537.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.62 (t, J=6.0 Hz, 1H), 7.55 (t,J=6.8 Hz, 1H), 7.39 (d, J=2.2 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.28-7.22(m, 2H), 7.13 (d, J=8.0 Hz, 2H), 7.02 (d, J=8.0, 2H), 6.96 (dd, J=8.6,2.5 Hz, 1H), 6.20 (s, 1H), 4.54 (t, J=7.8 Hz, 1H), 3.58 (dd, J=15.2, 7.8Hz, 1H), 3.19 (dd, J=15.2, 7.5 Hz, 1H), 2.35 (s, 3H).

Example 22

3-[1-(4-Methoxy-phenyl)-5-(4-phenoxy-phenyl)-1H-pyrazol-3-yl]-2-(4-trifluoromethoxyl-phenyl)-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=3.60 (MethodB). MS (ES+): mass calculated for C₃₂H₂₅F₃N₂O₅, 574.17; m/z found 575.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.42-7.38 (m, 2H), 7.36-7.31 (m, 2H),7.21-7.12 (m, 5H), 7.11-7.07 (m, 2H), 7.03-6.99 (m, 1H), 6.89-6.81 (m,4H), 6.18 (s, 1H), 4.18 (dd, J=9.6, 5.3 Hz, 1H), 3.80 (s, 3H), 3.52 (dd,J=14.9, 9.4 Hz, 1H), 3.12 (dd, J=15.2, 5.6 Hz, 1H).

Example 23

3-[5-Benzo[1,3]dioxo-5-yl-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-(3-trifluoromethoxyl-phenyl)-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=3.28 (MethodB). MS (ES+): mass calculated for C₂₇H₂₁F₃N₂O₆, 526.14; m/z found 527.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.38-7.29 (m, 2H), 7.22-7.20 (m, 1H),7.15-7.11 (m, 3H), 6.86-6.82 (m, 2H), 6.70 (d, J=7.8 Hz, 1H), 6.60 (dd,J=8.34, 1.5 Hz, 1H), 6.54 (d, J=1.8 Hz, 1H), 6.13 (s, 1H), 5.94 (s, 2H),4.13 (dd, J=8.6, 6.3 Hz, 1H), 3.81 (s, 3H), 3.52 (dd, J=14.9, 8.6 Hz,1H), 3.16 (dd, J=15.2, 6.8 Hz, 1H).

Example 24

3-[1-(3,4-Dichloro-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-(3-iodo-phenyl)-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=3.89 (MethodB). MS (ES+): mass calculated for C₂₅H₁₉Cl₂IN₂O₂, 575.99; m/z found577.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.73 (t, J=2.0 Hz, 1H), 7.64-7.62(m, 1H), 7.48 (d, J=2.5 Hz, 1H), 7.38-7.35 (m, 1H), 7.32 (d, J=8.6 Hz,2H), 7.15-7.07 (m, 4H), 6.98 (dd, J=8.8, 2.3 Hz, 1H), 6.18 (s, 1H), 4.11(dd, J=9.0, 6.3 Hz, 1H), 3.49 (dd, J=15.4, 8.8 Hz, 1H), 3.10 (dd,J=15.4, 6.3 Hz, 1H), 2.35 (s, 3H).

Example 25

3-[1-(3,4-Dichloro-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-(3,5-dimethyl-phenyl)-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=3.84 (MethodB). MS (ES+): mass calculated for C₂₇H₂₄Cl₂N₂O₂, 478.12; m/z found 479.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.45 (d, J=2.2 Hz, 1H), 7.35 (d, J=8.6Hz, 1H), 7.12 (d, J=7.8 Hz, 2H), 7.06-7.03 (m, 2H), 7.00-6.98 (m, 2H),6.97 (d, J=2.3 Hz, 1H), 6.93 (br, s, 1H), 6.22 (s, 1H), 4.05 (dd, J=6.0,5.6 Hz, 1H), 3.51 (dd, J=15.2, 9.3 Hz, 1H), 3.09 (dd, J=15.2, 5.8 Hz,1H), 2.36 (s, 3H), 2.31 (s, 6H).

Example 26

3-[1-(3,4-Dichloro-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-(3-trifluoromethylsulfanyl-phenyl)-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=3.91 (MethodB). MS (ES+): mass calculated for C₂₆H₁₉Cl₂F₃N₂O₂S, 550.05; m/z found551.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.67-7.65 (m, 1H), 7.61-7.57 (m,1H), 7.55-7.51 (m, 1H), 7.45 (d, J=2.5 Hz, 1H), 7.41 (t, J=7.1 Hz, 1H),7.32 (d, J=8.3 Hz, 2H), 7.12 (d, J=8.3 Hz, 2H), 7.04-7.01 (m, 2H), 6.95(dd, J=8.6, 2.3 Hz, 1H), 6.15 (s, 1H), 4.19 (dd, J=8.6, 6.3 Hz, 1H),3.53 (dd, J=15.4, 8.3 Hz, 1H), 3.16 (dd, J=14.9, 6.3 Hz, 1H), 2.37 (s,3H).

Example 27

3-[5-Benzo[1,3]dioxol-5-yl-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=9.47 (MethodA). MS (ES+): mass calculated for C₃₀H₂₄N₂O₅, 492.17; m/z found 493.2{M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.13 (d, J=8.6 Hz, 1H), 7.88-7.84 (m,2H), 7.79 (d, J=7.8 Hz, 1H), 7.58 (d, J=7.3 Hz, 1H), 7.51-7.43 (m, 3H),7.08(d, J=8.8 Hz, 1H), 6.80 (d, J=8.6 Hz, 2H), 6.6 (d, J=8.1 Hz, 1H),6.53 (dd, J=8.1, 1.26 Hz, 1H), 6.46 (d, J=1.8 Hz, 1H), 6.09 (s, 1H),5.93 (s, 2H), 4.95 (dd, J=8.6, 6.3 Hz, 1H), 3.79 (s, 3H), 3.73-3.65 (m,1H), 3.25 (dd, J=14.6, 6.3 Hz, 1H).

Example 28

(R)-3-[5-Benzo[1,3]dioxol-5-yl-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-propionicacid

The racemate (Example 27) was prepared by Method 2, and the titlecompound was isolated by semi-preparative chiral HPLC (Method D). HPLC:R_(t)=3.82 (Method C). MS (ES+): mass calculated for C₃₀H₂₄N₂O₅, 492.17;m/z found 493.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.83-7.79 (m, 4H), 7.52(dd, J=8.4, 1.6 Hz, 1H), 7.48-7.45 (m, 2H), 7.16-7.12 (m, 2H), 6.84-6.80(m, 2H), 6.70-6.68 (m, 1H), 6.62 (dd, J=7.8, 2.0 Hz, 2H), 6.56 (d, J=1.8Hz, 1H), 6.16 (s, 1H), 5.94 (s, 2H), 4.33 (dd, J=9.2, 5.6 Hz, 1H), 3.79(s, 3H), 3.63 (dd, J=14.9, 9.0 Hz, 1H), 3.24 (dd, J=15.7, 5.1 Hz, 1H).

Example 29

(S)-3-[5-Benzo[1,3]dioxol-5-yl-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-propionicacid

The racemate (Example 27) was prepared by Method 2, and the titlecompound was isolated by semi-preparative chiral HPLC (Method D). HPLC:R_(t)=6.83 (Method C). MS (ES+): mass calculated for C₃₀H₂₄N₂O₅, 492.17;m/z found 493.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.83-7.79 (m, 4H), 7.52(dd, J=8.4, 1.6 Hz, 1H), 7.48-7.45 (m, 2H), 7.16-7.12 (m, 2H), 6.84-6.80(m, 2H), 6.70-6.68 (m, 1H), 6.62 (dd, J=7.8, 2.0 Hz, 2H), 6.56 (d, J=1.8Hz, 1H), 6.16 (s, 1H), 5.94 (s, 2H), 4.33 (dd, J=9.2, 5.6 Hz, 1H), 3.79(s, 3H), 3.63 (dd, J=14.9, 9.0 Hz, 1H), 3.24 (dd, J=15.7, 5.1 Hz, 1H).

Example 30

3-[1,5-Bis-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-(3-methoxy-phenyl)-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=9.15 (MethodA). MS (ES+): mass calculated for C₂₇H₂₆N₂O₅, 458.18; m/z found 459.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.26-7.22 (m, 2H), 7.16-7.13 (m, 2H),7.08-7.05 (m, 2H), 6.97 (d, J=7.3 Hz, 1H), 6.93 (t, J=2.3 Hz, 1H),6.83-6.77 (m, 5H), 6.16 (s, 1H), 4.12 (dd, J=9.9, 5.3 Hz, 1H), 3.80 (s,3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.52 (dd, J=14.2, 9.6 Hz, 1H), 3.12(dd, J=15.2, 6.1 Hz, 1H).

Example 31

(R)-3-[1,5-Bis-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-(3-methoxy-phenyl)-propionicacid

The racemate (Example 30) was prepared by Method 2, and the titlecompound was isolated by semi-preparative chiral HPLC (Method D). HPLC:R_(t)=4.84 (Method C). MS (ES+): mass calculated for C₂₇H₂₆N₂O₅, 458.18;m/z found 459.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.28-7.24 (m, 2H),7.19-7.15 (m, 2H), 7.09-7.05 (m, 2H), 6.97 (d, J=7.8 Hz, 1H), 6.93 (t,J=2.0 Hz, 1H), 6.87-6.78 (m, 5H), 6.16 (s, 1H), 4.12 (dd, J=9.9, 6.2 Hz,1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.52 (dd, J=15.1, 9.5 Hz,1H), 3.12 (dd, J=15.3, 5.5 Hz, 1H).

Example 32

(S)-3-[1,5-Bis-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-(3-methoxy-phenyl)-propionicacid

The racemate (Example 30) was prepared by Method 2, and the titlecompound was isolated by semi-preparative chiral HPLC (Method D). HPLC:R_(t)=7.37 (Method C). MS (ES+): mass calculated for C₂₇H₂₆N₂O₅, 458.18;m/z found 459.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.28-7.24 (m, 2H),7.19-7.15 (m, 2H), 7.09-7.05 (m, 2H), 6.97 (d, J=7.8 Hz, 1H), 6.93 (t,J=2.0 Hz, 1H), 6.87-6.78 (m, 5H), 6.20 (s, 1H), 4.15 (dd, J=9.9, 6.2 Hz,1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.55 (dd, J=15.1, 9.5 Hz,1H), 3.16 (dd, J=15.3, 5.5 Hz, 1H).

Example 33

2-Biphenyl-4-yl-3-[5-(4-chloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=7.21 (MethodA). MS (ES+): mass calculated for C₃₁H₂₅N₂O₃, 508.16; m/z found 509.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.24-7.01 (m, 7H), 6.98-6.80 (m, 4H),6.75-6.64 (m, 2H), 6.58-6.44 (m, 2H), 5.79 (s, 1H), 3.71 (m, 1H), 3.47(s, 3H), 3.22-3.08 (m, 3H), 2.85-2.64 (m, 3H).

Example 34

3-[5-(4-Chloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-p-tolyl-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=10.11 (MethodA). MS (ES+): mass calculated for C₂₆H₂₃ClN₂O₃, 446.14; m/z found 447.2{M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.37 (br s, 1H), 7.40 (d, J=8.6 Hz,2H), 7.26 (d, J=8.1 Hz, 2H), 7.18-7.11 (m, 6H), 6.95 (d, J=9.0 Hz, 2H),6.40 (s, 1H), 3.98 (dd, J=6.3, 9.1 Hz, 1H), 3.77 (s, 3H), 3.34 (dd,J=9.1, 15.1 Hz, 1H), 2.92 (dd, J=6.2, 15.0 Hz, 1H), 2.27 (s, 3H).

Example 35

3-[5-(4-Chloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=10.11 (MethodA). MS (ES+): mass calculated for C₂₆H₂₃ClN₂O₃, 446.14; m/z found 447.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.29 (br s, 1H), 7.40 (d, J=8.6 Hz,2H), 7.22 (t, J=7.5 Hz, 1H), 7.19-7.15 (m, 3H), 7.13 (d, J=8.9 Hz, 2H),7.08 (d, J=7.3 Hz, 1H), 6.95 (d, J=9.0 Hz, 2H), 6.40 (s, 1H), 3.98 (dd,J=6.0, 9.3 Hz, 1H), 3.77 (s, 3H), 2.92 (dd, J=6.0, 14.9 Hz, 1H), 2.30(s, 3H).

Example 36

3-[5-(4-Chloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-(3-methoxy-phenyl)-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=9.79 (MethodA). MS (ES+): mass calculated for C₂₆H₂₃ClN₂O₄, 462.13; m/z found 463.1{M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.29 (br s, 1H), 7.40 (d, J=8.5 Hz,2H), 7.26 (t, J=7.9 Hz, 1H), 7.17 (d, J=8.5 Hz 2H), 7.13 (d, J=8.9 Hz,2H), 6.96-6.92 (m, 4H), 6.84 (d, J=8.2 Hz, 1H), 6.42 (s, 1H), 4.01 (dd,J=6.1, 9.2 Hz, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 2.93 (dd, J=6.1, 14.9Hz, 1H).

Example 37

2-(3-Chloro-phenyl)-3-[5-(4-chloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=10.19 (MethodA). MS (ES+): mass calculated for C25H₂₀Cl₂N₂O₃, 466.09; m/z found 467.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.45 (m, 1H), 7.43 (d, J=8.6 Hz, 2H),7.39-7.34 (m, 3H), 7.18 (d, J=8.6 Hz, 2H), 7.13 (d, J=9.0 Hz, 2H), 6.97(d, J=9.0 Hz, 2H), 4.11 (dd, J=6.8, 8.6 Hz, 1H), 3.79 (s, 3H), 3.38 (dd,J=8.4, 14.8 Hz, 1H), 3.01 (dd, J=6.8, 14.8 Hz, 1H).

Example 38

3-[1-(4-Chloro-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-naphthalen-1-yl-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=10.66 (MethodA). MS (ES+): mass calculated for C₂₉H₂₃ClN₂O₂, 466.14; m/z found 467.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.52 (br s, 1H), 8.22 (d, J=8.3 Hz,1H), 7.95 (d, J=8.0 Hz, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.60-7.52 (m, 4H),7.44 (d, J=8.9 Hz, 2H), 7.17-7.15 (m, 4H), 7.02 (d, J=8.1 Hz, 2H), 6.40(s, 1H), 4.87 (dd, J=6.3, 8.6 Hz, 1H), 3.54 (dd, J=8.6, 14.9 Hz, 1H),3.09 (dd, J=6.2, 14.9 Hz, 1H), 2.28 (s, 3H).

Example 39

2-(3-Chloro-phenyl)-3-[1-(3-chloro-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=10.56 (MethodA). MS (ES+): mass calculated for C₂₅H₂₀Cl₂N₂O₂, 450.09; m/z found 451.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.59 (br s, 1H), 7.44-7.31 (m, 7H),7.18 (d, J=8.0 Hz, 2H), 7.08 (d, J=8.1 Hz, 2H), 7.05 (d, J=7.2 HZ, 1H),6.38 (s, 1H), 4.10 (dd, J=6.8, 8.6 HZ, 1H), 3.00 (dd, J=6.7, 14.9 Hz,1H), 2.30 (s, 3H).

Example 40

3-(1,5-Di-p-tolyl-1H-pyrazol-3-yl)-2-m-tolyl-propionic acid

The title compound was prepared by Method 2: HPLC: R_(t)=10.30 (MethodA). MS (ES+): mass calculated for C₂₇H₂₆N₂O₂, 410.20; m/z found 411.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.39 (br s, 1H), 7.24-7.17 (m, 5H),7.13 (d, J=7.9 Hz, 2H), 7.09-7.02 (m, 5H), 6.32 (s, 1H), 3.98 (dd,J=6.0, 9.3 Hz, 1H), 2.92 (dd, J=6.0, 14.8 Hz, 1H), 2.31 (s, 3H), 2.30(s, 3H), 2.28 (s, 3H).

Example 41

2-Phenyl-3-[5-p-tolyl-1-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl]-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=10.41 (MethodA). MS (ES+): mass calculated for C₂₆H₂₁F₃N₂O₂, 450.16; m/z found 451.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.40 (br s, 1H), 7.76 (d, J=8.5 Hz,2H), 7.41-7.39 (m, 4H), 735 (t, J=7.7 Hz, 2H), 7.28 (m, 1H), 7.19 (d,7.9 Hz, 2H), 7.09 (d, J=8.1 Hz, 2H), 6.40 (s, 1H), 4.06 (dd, J=6.3, 9.1Hz, 1H), 3.40 (dd, J=9.0, 15 Hz, 1H), 2.98 (dd, J=6.3, 15 Hz, 1H), 2.31(s, 3H).

Example 42

3-[1-(3,4-Dichloro-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-(3-methoxy-phenyl)-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=10.61 (MethodA). MS (ES+): mass calculated for C₂₆H₂₂Cl₂N₂O₃, 480.10; m/z found 481.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.40 (br s, 1H), 7.62 (d J=8.7 Hz,1H), 7.53 (d, J=2.5 Hz, 1H), 7.26 (d, J=7.9 Hz, 1H), 7.20 (d, J=7.9 Hz,2H), 7.11 (d, J=8.1 Hz, 2H), 7.07 (dd, J=2.5, 8.6 Hz, 1H), 6.96 (d,J=7.7 Hz, 1H), 6.94 (s, 1H), 6.85 (dd, J=2.6, 8.3 Hz, 1H), 6.40 (s, 1H),4.03 (dd, J=6.1, 9.2 Hz, 1H), 3.74 (s, 3H), 3.36 (dd, J=9.3, 15.1 Hz,1H), 2.95 (dd, J=6.1, 15.0 Hz, 1H), 2.31 (s, 3H).

Example 43

3-(1-Benzyl-5-p-tolyl-1H-pyrazol-3-yl)-2-(2-chloro-phenyl)-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=9.95 (MethodA). MS (ES+): mass calculated for C₂₆H₂₃ClN₂O₂, 430.14; m/z found 431.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.60 (br s, 1H), 7.45-7.43 (m, 2H),7.32-7.28 (m, 2H), 7.23-7.15 (m, 7H), 6.83 (d, J=9.0 Hz, 2H), 6.12 (s,1H), 5.24 (s, 2H), 4.46 (t, J=7.8 Hz, 1H), 3.31 (dd, J=7.1, 14.6 Hz,1H), 3.04 (dd, J=8.2, 14.6 Hz, 1H), 2.29 (s, 3H).

Example 44

3-(1-Benzyl-5-p-tolyl-1H-pyrazol-3-yl)-2-(3-trifluoromethyl-phenyl)-propionicacid

The title compound was prepared by Method 2: HPLC: R_(t)=10.19 (MethodA). MS (ES+): mass calculated for C₂₇H₂₃F₃N₂O₂, 464.17; m/z found 465.0{M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.60 (br s, 1H), 7.65-7.63 (m, 4H),7.56 (t, J=7.9 Hz, 1H), 7.23-7.13 (m, 7H), 6.79 (m, 2H), 6.19 (s, 1H),5.23 (s, 2H), 4.17 (t, J=7.9 Hz, 1H), 3.32 (dd, J=7.5, 14.7 Hz, 1H),3.03 (dd, J=8.2, 14.7 Hz, 1H), 2.30 (s, 3H).

Example 45

3-(1-Benzyl-5-p-tolyl-1H-pyrazol-3-yl)-2-naphthalen-2-yl-propionic acid

The title compound was prepared by Method 2: HPLC: R_(t)=10.13 (MethodA). MS (ES+): mass calculated for C₃₀H₂₆N₂O₂, 446.20; m/z found 447.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.42 (br s, 1H), 7.90-7.85 (m, 4H),7.53-7.49 (m, 3H), 7.20-7.14 (m, 7H), 7.09 (t, J=7.6 Hz, 2H), 6.78 (d,J=7.3 Hz, 2H), 6.20 (s, 1H), 5.23 (s, 2H), 4.18 (t, J=7.8 Hz, 1H), 3.40(dd, J=7.8, 14.8 Hz, 1H), 3.09 (dd, J=7.8, 14.7 Hz, 1H), 2.29 (s, 3H).

Example 46

2-(2,3-Dichloro-phenyl)-3-[1-(3,4-dichloro-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-propionicacid

A. 1,2 Dichloro-3-(2-methanesulfinyl-2-methylsufanyl-vinyl)-benzene. Toa stirred solution of methyl methylthiomethyl sulfoxide (4.97 g, 40.0mmol) and 2,3-dichlorobenzaldehyde (5.00 g, 28.6 mmol) in 10 mL of THFwas added 4 mL of triton-B (40% in MeOH). The resultant mixture wasrefluxed for 4 h. The solvent was removed under reduced pressure, andthe residue was purified by silica gel chromatography (5:95EtOAc/hexane) to afford 5.4 g (67.5%) of1,2-dichloro-3-(2-methanesulfinyl-2-methylsufanyl-vinyl)-benzene. HPLC:R_(t)=8.99. (Method A). ¹H NMR (400 MHz, CDCl₃): 7.86 (s, 1H), 7.73 (dd,J=8.4, 0.9 Hz, 1H), 7.47 (dd, J=9.0, 0.6 Hz, 1H), 7.38-7.23 (m, 1H),2.83 (s, 3H), 2.24 (s, 3H).

B. (2,3-Dichloro-phenyl)-acetic acid ethyl ester. A stirred solution of1,2-dichloro-3-(2-methanesulfinyl-2-methylsufanyl-vinyl)-benzene (5.40g, 19.3 mmol) in 30 mL of MeOH at 0° C. was bubbled with HCl gas for 10min and then was allowed to warm to rt and stir for 0.5 h. The solventwas removed under reduced pressure, and the residue was purified bysilica gel chromatography (5:95 EtOAc/hexane) to afford 3.08 g (73.4%)of (2,3-Dichloro-phenyl)-acetic acid ethyl ester. HPLC: R_(t)=9.88(Method A). ¹H NMR (400 MHz, CDCl₃): 7.40 (dd, J=7.2, 2.7 Hz, 1H),7.20-7.15 (m, 2H), 4.18 (dd, J=14.2, 7.0 Hz, 2H), 3.79 (s, 2H), 1.26 (t,J=6.8, Hz, 2H).

C.2-(2,3-Dichloro-phenyl)-3-[1-(3,4-dichloro-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-propionicacid. The title compound was prepared by Method 2 (Scheme A) from theproduct of Step B and the appropriate pyrazole bromide from Method 1:HPLC: R_(t)=3.89 (Method B). MS (ES+): mass calculated forC₂₅H₁₈Cl₄N₂O₂, 518.01; m/z found 519.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.43 (d, J=2.3 Hz, 1H), 7.40 (dd, J=8.6, 1.5 Hz, 1H), 7.36 (dd, J=7.8,1.2 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.21 (t, J=8.1 Hz, 2H), 7.12 (d,J=8.8 Hz, 2H), 7.05-7.02 (m, 2H), 6.96 (dd, J=8.6, 2.5 Hz, 1H), 6.18 (s,1H), 4.76 (dd, J=8.3, 6.6 Hz, 1H), 3.52 (dd, J=15.4, 8.1 Hz, 1H), 3.16(dd, J=14.9, 7.3 Hz, 1H), 2.35 (s, 3H).

Method 3

Synthesis of 4-Oxo-2-aryl-pentanoic Acids, Such as

A. 2-m-Tolyl-pent-4-enoic acid ethyl ester. To a stirred solution3-methylphenylacetic acid ethyl ester (50.0 g, 0.281 mol) in DMF (500mL) at 0° C. under N₂ was added 60% NaH (12.3 g, 0.308 mol) in smallportions. The mixture was allowed to warm to rt and stir for 1.5 h. In asecond vessel, a stirred solution of allyl bromide (72.7 mL, 0.843 mol)in DMF (300 mL) was cooled to −42° C. (acetonitrile/CO₂) under N₂, andthe enolate mixture was slowly added to this solution by cannula. Afterthe addition was complete, the mixture was allowed to warm to rt andstir for 2 h. The mixture was then diluted with H₂O (100 mL) and themajority of the DMF was removed under reduced pressure. The mixture wasthen further diluted with H₂O (400 mL) and EtOAc (500 mL), and thelayers were separated. The aqueous phase was extracted with EtOAc (3×150mL) and the combined organic extracts were dried over Na₂SO₄ andfiltered, and the solvent was removed under reduced pressure.Purification on silica gel (0-10% EtOAc in hexane) gave 57.4 g (93%) ofdesired ester as a light yellow oil. TLC (silica, 10% EtOAc/hexane):R_(f)=0.7. ¹H NMR (400 MHz, CDCl₃): 7.21 (t, J=7.8 Hz, 1H), 7.12 (s,1H), 7.08 (t, J=7.8 Hz, 2H), 5.79-5.66 (m, 1H), 5.11-5.04 (m, 1H),5.02-4.98 (m, 1H), 4.20-4.02 (m, 2H), 3.62-3.54 (m, 1H), 2.86-2.74 (m,1H), 2.53-2.44 (m, 1H), 2.34 (s, 3H), 1.21 (t, J=7.1 Hz, 3H).

B. 4-Oxo-2-m-tolyl-pentanoic acid ethyl ester. A slow stream of O₂ wasbubbled through a stirred suspension of 2-m-tolyl-pent-4-enoic acidethyl ester (57.0 g, 0.261 mol), CuCl (25.7 g, 0.261 mol) and PdCl₂(9.26 g, 0.052 mol) in 8:1 DMF/H₂O (130 mL) for 14 h. The mixture wasdiluted with CH₂Cl₂ (500 mL) and 9:1 saturated NH₄Cl/NH₄OH (500 mL). Themixture was stirred for 1 h and then filtered through a pad of celite.The layers were separated, and the organic phase was washed with 9:1saturated NH₄Cl/NH₄OH (200 mL). The combined aqueous phases wereextracted with CH₂Cl₂ (3×150 mL). The organics were then dried overNa₂SO₄ and filtered, and the solvent was removed under reduced pressure.Purification on silica gel (0-20% EtOAc in hexane) gave 34.4 g (56%) ofdesired ketone as a light yellow oil. TLC (silica, 10% EtOAc/hexane):R_(f)=0.3. ¹H NMR (400 MHz, CDCl₃): 7.20 (t, J=7.6 Hz, 1H), 7.10-7.03(m, 3H), 4.20-4.00 (m, 3H), 3.37 (dd. J=10.4, 17.9 Hz, 1H), 2.69 (dd.J=4.3, 17.9 Hz, 1H), 2.33 (s, 3H), 2.17 (s, 3H), 1.20 (t, J=7.3 Hz, 3H).

C. 4-Oxo-2-m-tolyl-pentanoic acid. To a stirred solution of4-oxo-2-m-tolyl-pentanoic acid ethyl ester (34.0 g, 145 mmol) in 3:1:1THF/MeOH/H₂O (300 mL) was added LiOH.H₂O (30.5 g, 0.726 mol) and themixture was stirred overnight at rt. The mixture was then heated to 65°C. for 2 h, cooled to rt, and was diluted with H₂O (250 mL) and 20%diethyl ether/hexane. The layers were separated, and the aqueous layerwas adjusted to pH 1 with concd HCl at 0° C. The aqueous phase was thenextracted with EtOAc (3×200 mL), dried over Na₂SO₄ and filtered, andthen the solvent was removed under reduced pressure to afford 28.4 g(95%) of crude acid as a light yellow solid. TLC (silica, 10%EtOAc/hexane): R_(f)=0.3. ¹H NMR (400 MHz, CDCl₃): 7.21 (t, J=7.6 Hz,1H), 7.11-7.05 (m, 3H), 4.08 (dd. J=4.0, 10.2 Hz, 1H), 3.35 (dd. J=10.2,18.2 Hz, 1H), 2.70 (dd. J=4.0, 18.2 Hz, 1H), 2.34 (s, 3H), 2.17 (s, 3H).

Method 4

Synthesis of 3-(1,5-Disubstituted-1H-pyrazol-3-yl)-2-aryl-propionicAcids and 3-(2,5-Disubstituted-4H-pyrazol-5-yl)-2-aryl-propionic Acids,Such as

Scheme E. To a slurry of 10.0 g of 4-sulfamylbenzoyl AM resin(NovaBiochem, 1.21 mmol/g) in 1:1 THF/CH₂Cl₂ (70 mL) was added DMAP(0.201 g, 1.65 mmol), 4-oxo-2-m-tolyl-pentanoic acid (E1) (17.7 g, 86.0mmol) prepared by Method 3, N,N-diisopropylethylamine (7.51 mL, 43.0mmol), and diisopropylcarbodiimide (6.72 mL, 43.0 mmol). The mixture wasshaken overnight, and the filtrate was drained under reduced pressure.The resin was then washed (3×5 mL) with 1:1 THF/CH₂Cl₂, MeOH, DMF, MeOH,and THF and then dried under vacuum overnight to give the coupled resinE2 (theoretical loading: 0.98 mmol/g). The resin was then loaded into a48-position Bohdan miniblock (˜200 mg/well) along with the appropriateester E5 (3.60 mmol, 18 equiv), and the inert atmosphere manifold wasadded (N₂). To each well was then added 1.0 M NaHMDS in THF (3.63 mmol,18 equiv), and the block was heated to 50° C. overnight. The block wascooled, the solvent was removed under reduced pressure, and each wellwas washed (3×5 mL) with cold 4:1 AcOH/H₂O, THF, DMF, and MeOH. Afterthe resin was dried under reduced pressure, the appropriate hydrazinesE6 (2.40 mmol, 12.equiv) were then loaded into the wells of the blockfollowed by MeOH (3.0 mL), providing a unique resin in each of the 48wells of the block, and the reaction mixtures were heated to 65° C. andshaken overnight. The block was cooled, the solvent was removed underreduced pressure, and each well was washed (3×5 mL) with THF,-MeOH, andTHF. After the resin was dried under reduced pressure, THF (1.0 mL) wasadded to each well followed by 1.0 M (trimethylsilyl)diazomethane(TMSCHN₂) in hexane (1.0 mmol, 10 equiv), and the block was shaken for 1h. The filtrates were drained under reduced pressure, and the TMSCHN₂treatment was repeated. The resin was then diluted with 3:1:1THF/MeOH/H₂O (2.5 mL/well), LiOH.H₂O (1.0 mmol, 10 equiv) was added toeach well, and the block was heated to 50° C. overnight. The block wascooled and the reaction mixtures were drained into a 48-well Beckmanplate. The resin was then washed with MeOH, DMF and THF (3.0 mL each),each wash being drained into a 48-well plate, and the solvent wasremoved under reduced pressure. The plated compounds were dissolved inDMF (1.5 mL total volume/well), and identical compounds were combinedand purified on a Gilson 215 prep-HPLC system (Method G) giving thedesired acids (A9) (0.5-7.0 mg, isolated as TFA salt) as well as, insome cases, the other regioisomer of the pyrazole. The 1,5-disubstitutedand the 2,5-disubstituted pyrazole regioisomers were isolated andcharacterized, and the isomer structures were confirmed by assignment ofCOSY and NOESY spectra. For the 2,5-disubstituted pyrazole regioisomer,enhancement was observed between the N-aryl protons and the alkylside-chain.

Example 47

3-(5-Naphthalen-2-yl-1H-pyrazol-3-yl)-2-m-tolyl-propionic acid

The title compound was prepared by Method 4: HPLC: R_(t)=2.91 (MethodB). MS (ES+): mass calculated for C₂₃H₂₀N₂O₂, 356.15; m/z found, 357.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.08 (s, 1H), 7.87-7.70 (m, 4H),7.49-7.41 (m, 2H), 7.36-7.23 (m, 4H), 7.19 (d, J=7.1 Hz, 1H), 6.58 (s,1H), 3.95 (d, J=11.9 Hz, 1H), 3.66 (t, J=12.6 Hz, 1H), 3.05 (d, J=13.6Hz, 1H), 2.42 (s, 3H).

Example 48

3-[5-(3,4-Dichloro-phenyl)-2-methyl-2H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The title compound was prepared by Method 4: HPLC: R_(t)=3.30 (MethodB). MS (ES+): mass calculated for C₂₀H₁₈Cl₂N₂O₂, 388.07; m/z found,388.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.81 (d, J=2.0 Hz, 1H), 7.54 (dd,J=8.3, 2.0 Hz, 1H) 7.42 (d, J=8.0 Hz, 1H), 7.16-7.10 (m, 4H), 6.30 (s,1H), 3.92 (dd, J=8.9, 6.1 Hz, 1H), 3.74 (s, 3H), 3.45 (dd, J=15.4, 8.9Hz, 1H), 3.00 (dd, J=15.4, 6.1 Hz, 1H), 2.35 (s, 3H).

Example 49

3-[5-(3,4-Dichloro-phenyl)-1-methyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The title compound was prepared by Method 4: HPLC: R_(t)=3.18 (MethodB). MS (ES+): mass calculated for C₂₀H₁₈Cl₂N₂O₂, 388.07; m/z found,388.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.50 (d, J=8.3 Hz, 1H), 7.45 (d,J=2.3 Hz, 1H), 7.24-7.14 (m, 4H), 7.10 (d, J=7.6 Hz, 1H), 6.03 (s, 1H),4.03 (dd, J=9.7, 5.5 Hz, 1H), 3.79 (s, 3H), 3.46 (dd, J=14.9, 9.7 Hz,1H), 3.03 (dd, J=14.9, 5.5 Hz, 1H), 2.34 (s, 3H).

Example 50

3-(2-Cyclohexyl-5-naphthalen-2-yl-2H-pyrazol-3-yl)-2-m-tolyl-propionicacid

The title compound was prepared by Method 4: HPLC: R_(t)=3.71 (MethodB). MS (ES+): mass calculated for C₂₉H₃₀N₂O₂, 438.23; m/z found, 439.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.20 (s, 1H), 7.88-7.78 (m, 4H),7.51-7.44 (m, 2H), 7.28-7.22 (m, 1H), 7.18-7.11 (m, 3H), 6.48 (s, 1H),4.08 (app tt, J=11.9, 3.5 Hz, 1H), 3.97 (dd, J=8.5, 6.8 Hz, 1H), 3.52(dd, J=15.4, 8.5 Hz, 1H), 3.08 (dd, J=15.4, 6.8 Hz, 1H), 2.35 (s, 3H),2.15-1.99 (m, 2H), 1.97-1.80 (m, 3H), 1.75-1.58 (m, 2H), 1.45-1.16 (m,3H).

Example 51

3-(1-Cyclohexyl-5-naphthalen-2-yl-1H-pyrazol-3-yl)-2-m-tolyl-propionicacid

The title compound was prepared by Method 4: HPLC: R_(t)=3.56 (MethodB). MS (ES+): mass calculated for C₂₉H₃₀N₂O₂, 438.23; m/z found, 439.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.95-7.85 (m, 3H), 7.79 (s, 1H),7.60-7.55 (m, 2H), 7.38 (dd, J=8.3, 1.8 Hz, 1H), 7.24-7.12 (m, 3H), 7.08(d, J=7.3 Hz, 1H), 6.10 (s, 1H), 4.18 (dd, J=9.5, 4.8 Hz, 1H), 4.14 (apptt, J=11.6, 3.8 Hz, 1H), 3.53 (dd, J=15.3, 9.5 Hz, 1H), 3.17 (dd,J=15.3, 4.8 Hz, 1H), 2.33 (s, 3H), 2.14-1.77 (m, 6H), 1.67-1.58 (m, 1H),1.31-1.11 (m, 3H).

Example 52

3-(5-Naphthalen-2-yl-1-pyridin-2-yl-1H-pyrazol-3-yl)-2-m-tolyl-propionicacid

The title compound was prepared by Method 4: HPLC: R_(t)=3.21 (MethodB). MS (ES+): mass calculated for C₂₈H₂₃N₃O₂, 433.18; m/z found, 434.2{M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.34 (d, J=4.3 Hz, 1H), 7.83-7.62 (m,5H), 7.52-7.45 (m, 2H), 7.33 (d, J=8.1 Hz,1H), 7.29-7.14 (m, 5H),7.13-7.03 (m,1H), 6.34 (s, 1H), 4.17 (dd, J=9.6, 5.5 Hz, 1H), 3.60 (dd,J=14.9, 9.6 Hz, 1H), 3.16 (dd, J=14.9, 5.5 Hz, 1H), 2.35 (s, 3H).

Example 53

3-[1-(4-tert-Butyl-phenyl)-5-(4-phenoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The title compound was prepared by Method 4: HPLC: R_(t)=3.87 (MethodB). MS (ES+): mass calculated for C₃₅H₃₄N₂O₃, 530.26; m/z found, 531.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.40-7.05 (m, 13H), 7.02 (d, J=7.9 Hz,2H), 6.87 (d, J=8.8 Hz, 2H), 6.20 (s, 1H), 4.10 (dd, J=9.5, 5.6 Hz, 1H),3.54 (dd, J=14.9, 9.5 Hz, 1H), 3.12 (dd, J=14.9, 5.6 Hz, 1H), 2.34 (s,3H), 1.29 (s, 9H).

Example 54

3-[5-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The title compound was prepared by Method 4: HPLC: R_(t)=3.24 (MethodB). MS (ES+): mass calculated for C₂₆H₂₂Cl₂N₂O₄S, 528.07; m/z found,529.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.90 (d, J=8.6 Hz, 2H), 7.43 (d,J=8.6 Hz, 2H), 7.39 (d, J=8.5 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.28-7.17(m, 3H), 7.13 (d, J=7.4 Hz, 1H), 6.92 (dd, J=8.4, 2.0 Hz, 1H), 6.27 (s,1H), 4.12 (dd, J=9.5, 5.8 Hz, 1H), 3.54 (dd, J=15.2, 9.5 Hz, 1H), 3.11(dd, J=15.2, 5.8 Hz, 1H), 3.06 (s, 3H), 2.34 (s, 3H).

Example 55

3-[5-Benzo[1,3]dioxol-5-yl-1-(2-chloro-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The title compound was prepared by Method 4: HPLC: R_(t)=3.12 (MethodB). MS (ES+): mass calculated for C₂₆H₂₁ClN₂O₄, 460.12; m/z found, 461.0[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.44-7.14 (m, 7H), 7.09 (d, J=7.1 Hz,1H), 6.66 (d, J=7.8 Hz, 1H), 6.61-6.55 (m, 2H), 6.18 (s, 1H), 5.92 (s,2H), 4.09 (dd, J=8.9, 6.3 Hz, 1H), 3.52 (dd, J=14.9, 8.9 Hz, 1H), 3.14(dd, J=14.9, 6.3 Hz, 1H), 2.33 (s, 3H).

Example 56

3-[1-(2,4-Dichloro-phenyl)-5-pyridin-3-yl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The title compound was prepared by Method 4: HPLC: R_(t)=2.50 (MethodB). MS (ES+): mass calculated for C₂₄H₁₉Cl₂N₃O₂, 451.09; m/z found,452.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.60 (s, 1H), 8.58 (s, 1H), 7.56(d, J=8.1 Hz, 1H), 7.44-7.30 (m, 4H), 7.24-7.15 (m, 3H), 7.10 (d, J=7.4Hz, 1H), 6.44 (s, 1H), 4.09 (dd, J=9.3, 6.0 Hz, 1H), 3.55 (dd, J=14.9,9.3 Hz, 1H), 3.15 (dd, J=14.9, 6.0 Hz, 1H), 2.34 (s, 3H).

Example 57

3-[5-(3-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The title compound was prepared by Method 4: HPLC: R_(t)=3.53 (MethodB).

MS (ES+): mass calculated for C₂₅H₁₉Cl₃N₂O₂, 484.05; m/z found, 485.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.42 (s, 1H), 7.32-7.13 (m, 8H), 7.10(d, J=7.1 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.26 (s, 1H), 4.10 (dd,J=9.1, 6.3 Hz, 1H), 3.52 (dd, J=14.9, 9.1 Hz, 1H), 3.13 (dd, J=14.9, 6.3Hz, 1H), 2.34 (s, 3H).

Method 5

Synthesis of 4-(4-Oxo-2-aryl-pentanoylsulfamoyl)-benzoic Acids, such as:

4-(4-Oxo-2-m-tolyl-pentanoylsulfamoyl)-benzoic acid

A. 4-Sulfamoyl-benzoic acid methyl ester. To a stirred suspension of4-sulfamoyl-benzoic acid (25.0 g, 0.124 mol) in 4:1 CH₂Cl₂/MeOH at rtwas added 1.0 M TMSCHN₂ in hexane (175 mL), and the reaction mixture wasallowed to stir for 2 h. The mixture was diluted with 1N NaOH (100 mL)and CH₂Cl₂ (150 mL), and the layers were separated. The organic layerwas dried over Na₂SO₄, then filtered, and the solvent was removed underreduced pressure to afford the desired ester (25.2 g, 95%), which wasused without further purification. ¹H NMR (400 MHz, DMSO-d₆): 8.14 (d,J=8.1 Hz, 2H), 7.96 (d, J=8.1 Hz, 2H), 7.58 (s, 2H), 3.90 (s, 3H).

B. 4-(4-Oxo-2-m-tolyl-pentanoylsulfamoyl)-benzoic acid methyl ester. Toa stirred solution of 4-sulfamoyl-benzoic acid methyl ester (6.01 g,27.8 mmol), 4-oxo-2-m-tolyl-pentanoic acid (6.35 g, 30.7 mmol),N,N-diisopropylethylamine (12.2 mL, 69.5 mmol), and DMAP (5 mole %) inCH₂Cl₂ (275 mL) at rt under N₂ was addedbromo-tripyrrolidino-phosphonium hexafluorophosphate (PyBroP) (18.1 g,38.9 mmol), and the reaction mixture was allowed to stir overnight. Themixture was diluted with 1M HCl (100 mL) and CH₂Cl₂ (150 mL), and thelayers were separated. The organic phase was washed with 1M HCl (1×100mL), 1N NaOH (1×100 mL) and brine (1×100 mL). The organic layer wasdried over Na₂SO₄, and then filtered, and the solvent was removed underreduced pressure. Purification on silica gel (0-15% EtOAc in hexane)gave 12.0 g (99%) of desired ester as a white solid. ¹H NMR (400 MHz,CDCl₃): 8.15 (d, J=8.6 Hz, 2H), 7.99 (d, J=8.6 Hz, 2H), 7.18 (t, J=7.6Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 6.87 (m, 2H), 3.97 (s, 3H), 3.93 (dd.J=4.3 and 9.5 Hz, 1H), 3.29 (dd. J=9.5 and 18.1 Hz, 1H), 2.60 (dd. J=4.3and 18.1 Hz, 1H), 2.28 (s, 3H), 2.07 (s, 3H).

C. 4-(4-Oxo-2-m-tolyl-pentanoylsulfamoyl)-benzoic acid. To a stirredsolution of 4-(4-oxo-2-m-tolyl-pentanoylsulfamoyl)-benzoic acid methylester (12.0 g, 27.7 mmol) in 3:1:1 THF/MeOH/H₂O (110 mL) was addedLiOH.H₂O {5.84 g, 139 mmol), and the mixture was stirred overnight atrt. The mixture was then heated to 65° C. for 2 h, cooled to rt, andthen was diluted with H₂O (100 mL) and 20% diethyl ether/hexane. Thelayers were separated, and the aqueous layer was adjusted to pH 1 withconcd HCl at 0° C. The aqueous phase was then extracted with EtOAc(3×200 mL), dried over Na₂SO₄, and filtered, and the solvent was removedunder reduced pressure to afford 10.6 g (96%) of crude acid as a whitesolid. TLC (silica, 5% MeOH—CH₂Cl₂): R_(f)=0.2. ¹H NMR (400 MHz,DMSO-d₆): 8.06 (d, J=8.1 Hz, 2H), 7.96 (d, J=8.1 Hz, 2H), 7.16 (t, J=7.6Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.82 (s, 1H),3.89 (dd. J=3.9, 10.6 Hz, 1H), 3.14 (dd. J=10.6, 18.3 Hz, 1H), 2.70 (dd.J=3.9, 18.3 Hz, 1H), 2.19 (s, 3H), 2.00 (s, 3H).

Method 6

Synthesis of 3-(1,5-Disubstituted-1H-pyrazol-3-yl)-2-aryl-propionicAcids and 3-(2,5-Disubstituted-4H-pyrazol-5-yl)-2-aryl-propionic Acids,such as:

Scheme F. To a slurry of 5.0 g of 4-aminomethyl macroporous polystyreneresin (ArgoPore-NH₂—HL, 1.22 mmol/g) in THF (30 mL) was added HOBt (1.66g, 12.2 mmol), 4-(4-oxo-2-m-tolyl-pentanoylsulfamoyl)-benzoic acid (E1)(4.81 g, 12.2 mmol) prepared by Method 5, and diisopropylcarbodiimide(1.91 mL, 12.2 mmol). The mixture was shaken overnight and the filtratewas drained under reduced pressure. The resin was then washed (3×5 mL)with THF, CH₂Cl₂, MeOH, DMF and THF and then dried under vacuumovernight to give the coupled resin F3 (˜0.75 mmol/g based on elementalanalysis of sulfur). The resin was then loaded into a 48-position Bohdanminiblock (˜230 mg/well) along with the appropriate ester F6 (2.20 mmol,12.0 equiv), and the inert atmosphere manifold was added (N₂). To eachwell was then added 1.0 M NaHMDS in THF (1.80 mmol, 12 equiv), and theblock was heated to 50° C. overnight. The block was cooled, the solventwas removed under reduced pressure, and each well was washed (3×5 mL)with 5% TFA/THF, H₂O, THF, DMF, and MeOH. After the resin F4 was driedunder reduced pressure, the appropriate hydrazines F7 (1.80 mmol, 10equiv) were added to the wells followed by MeOH (3.0 mL) andN,N-diisopropylethylamine (0.32 mL, 1.8 mmol, for aryl hydrazines) orH₂SO₄ (2 drops, for alkyl hydrazines), creating a unique product in eachwell of the 48-well miniblock, and the reaction mixtures were heated to65° C. overnight. The block was cooled, the solvent was removed underreduced pressure, and each well was washed (3×5 mL) with 5% TFA/THF,THF, MeOH, DMF and THF. After the resin F5 was dried under reducedpressure, THF (1.0 mL) was added to each well followed by 1.0 M TMSCHN₂in hexane (1.0 mL, 14.0 equiv), and the block was shaken for 1 h. Thefiltrates were drained under reduced pressure and the TMSCHN₂ procedurewas repeated. The resin was then diluted with 2:1 2N NaOH/THF (2.5mL/well), and the block was heated to 50° C. overnight. The block wascooled, and the reaction mixtures were drained into a 48-well Beckmanplate. The resin was then washed with MeOH, DMF and THF (3.0 mL each),each wash being drained into a 48-well plate, and the solvent wasremoved under reduced pressure. The plated compounds were dissolved inDMF (1.5 mL total volume/well), and identical compounds were combinedand purified on a Gilson 215 prep-HPLC system (Method G) giving thedesired acids (A9) (3.0-11.0 mg, isolated as TFA salt) as well as, insome cases, the other regioisomer of the pyrazole. The 1,5-disubstitutedand the 2,5-disubstituted pyrazole regioisomers were isolated andcharacterized, and the isomer structures were confirmed by assignment ofCOSY and NOESY spectra. For the 2,5-disubstituted pyrazole regioisomer,enhancement was observed between the N-aryl protons and the alkylside-chain.

Example 58

3-[5-(4-Benzyloxy-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The title compound was prepared by Method 6: HPLC: R_(t)=3.58 (Method8). MS (ES+): mass calculated for C₃₃H₂₇F₃N₂O₄, 572.19; m/z found, 573.5[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.48-7.02 (m, 15H), 6.90 (d, J=8.6 Hz,2H), 6.18 (s, 1H), 5.05 (s, 2H), 4.11 (dd, J=9.6, 5.6 Hz, 1H), 3.53 (dd,J=14.9, 9.6 Hz, 1H), 3.11 (dd, J=14.9, 5.6 Hz, 1H), 2.34 (s, 3H).

Example 59

3-[5-(4-Dimethylamino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The title compound was prepared by Method 6: HPLC: R_(t)=2.65 (MethodB). MS (ES+): mass calculated for C₂₈H₂₉N₃O₂, 439.23; m/z found, 440.3[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.24-7.03 (m, 12H), 6.24 (s, 1H), 4.15(dd, J=9.9, 5.6 Hz, 1H), 3.54 (dd, J=14.9, 9.9 Hz, 1H), 3.30 (s, 3H),3.14 (dd, J=14.9, 5.6 Hz, 1H), 2.37 (s, 3H), 2.36 (s, 6H).

Example 60

3-[5-(3-Methoxy-4-methyl-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The title compound was prepared by Method 6: HPLC: R_(t)=3.30 (MethodB). MS (ES+): mass calculated for C₂₈H₂₈N₂O₃, 440.21; m/z found, 441.3[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.24-7.08 (m, 8H), 7.02 (d, J=7.6 Hz,1H), 6.69 (dd, J=7.6, 1.0 Hz, 1H), 6.54 (s, 1H), 6.21 (s, 1H), 4.14 (dd,J=9.4, 5.3 Hz, 1H), 3.58 (s, 3H), 3.54 (dd, J=15.0, 9.6 Hz, 1H), 3.14(dd, J=15.0, 5.3 Hz, 1H), 2.35 (s, 3H), 2.34 (s, 3H), 2.18 (s, 3H).

Example 61

3-[5-(3-Cyclopentyloxy-4-methoxy-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The title compound was prepared by Method 6: HPLC: R_(t)=3.33 (MethodB). MS (ES+): mass calculated for C₃₂H₃₄N₂O₄, 510.25; m/z found, 511.4[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.25-7.05 (m, 9H), 6.82-6.79 (m, 1H),6.50 (d, J=2.0 Hz, 1H), 6.20 (s, 1H), 4.39 (app tt, J=4.8, 4.8 Hz, 1H),4.15 (dd, J=9.8, 5.4 Hz, 1H), 3.83 (s, 3H), 3.55 (dd, J=15.0, 9.8 Hz,1H), 3.14 (dd, J=15.0, 5.4 Hz, 1H), 2.35 (s, 3H), 2.34 (s, 3H),1.76-1.68 (m, 2H), 1.67-1.59 (m, 4H), 1.55-1.45 (m, 2H).

Example 62

3-[5-(4-Bromo-3-methyl-phenyl)-1-(4-phenoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The title compound was prepared by Method 6: HPLC: R_(t)=3.69 (MethodB). MS (ES+): mass calculated for C₃₂H₂₇BrN₂O₃, 566.12; m/z found, 567.4[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.47-6.91 (m, 15H), 6.80 (dd, J=8.1,2.0 Hz, 1H), 6.23 (s, 1H), 4.13 (dd, J=9.7, 5.5 Hz, 1H), 3.54 (dd,J=14.9, 9.7 Hz, 1H), 3.13 (dd, J=14.9, 5.5 Hz, 1H), 2.35 (s, 3H), 2.33(s, 3H).

Example 63

3-[5-(7-Methoxy-benzofuran-2-yl)-1-(4-phenoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

The title compound was prepared by Method 6: HPLC: R_(t)=3.53 (MethodB). MS (ES+): mass calculated for C₃₄H₂₈N₂O₅, 544.20; m/z found, 545.4[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.43-7.35 (m, 3H), 7.31-7.01 (m, 12H),6.80 (d, J=7.8 Hz, 1H), 6.68 (s, 1H), 6.23 (s, 1H), 4.14 (dd, J=9.2, 5.8Hz, 1H), 3.98 (s, 3H), 3.54 (dd, J=14.9, 9.2 Hz, 1H), 3.14 (dd, J=14.9,5.8 Hz, 1H), 2.35 (s, 3H), 2.34 (s, 3H).

Example 64

N-(2-Hydroxy-cyclohexyl)-3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionamide

To a solution of3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid (product of Method 2) (100 mg, 0.23 mmol), EDC (65 mg, 0.35 mmol),and HOBT (46 mg, 0.34 mmol) in DMF (4.0 mL) was addedtrans-2-aminocyclohexanol hydrochloride (52 mg, 0.34 mmol) and DIEA(0.20 mL, 1.2 mmol). The reaction mixture was stirred for 24 h, dilutedwith EtOAc, and washed with 1.0 N NaOH (2×25 mL), water (1×25 mL), 5%formic acid (2×25 mL), water (1×25 mL) and brine (1×25 mL). The organiclayer was dried (Na₂SO₄) and the solvent was removed under reducedpressure. Reversed-phase HPLC afforded 40 mg (33%) ofN-(2-hydroxy-cyclohexyl)-3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionamideas a mixture of diastereomers. HPLC: R_(t)=3.17 (Method B). MS (ES+):mass calculated for C₃₃H₃₇N₃O₃, 523.28; m/z found 524.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.92-7.85 (m, 1H), 7.26-7.10 (m, 6H), 7.05-7.01 (m,3H), 6.94-6.91 (m, 2H), 6.32 (s, 0.5H), 6.29 (s, 0.5H), 4.42 (d, J=4.7Hz, 0.5H), 4.34 (d, J=5.4 Hz, 0.5H), 3.90 (ddd, J=5.4, 9.4, 20.3 Hz,1H), 3.76 (s, 3H), 3.24 (m, 0.5H), 3.17 (m, 0.5H), 2.85 (m, 1H), 2.30(s, 1.5H), 2.28 (s, 1.5H), 2.27 (s, 3H), 1.75 (m, 1H), 1.55 (m, 2H),1.13 (m, 4H), 0.97 (m, 1H).

Example 65

3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionamide

A mixture of3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid (product of Method 2) (0.10 g, 0.23 mmol) and CDI (85 mg, 0.52mmol) in DMF (2.5 mL) was stirred at rt for 30 min. The solution wasthen cooled to 0° C., and ammonium carbonate (99 mg, 1.0 mmol) was addedin portions. The reaction mixture was allowed to warm to rt and stirredfor an additional 18 h. The reaction mixture was then diluted with water(25 mL) and extracted with EtOAc (3×25 mL). Organic layers werecombined, washed with water (3×25 mL) and brine (1×25 mL) and dried withNa₂SO₄, and the solvent removed under reduced pressure giving 70 mg(71%) of the title compound. HPLC: R_(t)=9.38 (Method A). MS (ES+): masscalculated for C₂₇H₂₇N₃O₂, 425.21; m/z found 426.2 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): 7.50 (s, 1H), 7.22 (s, 1H), 7.20 (d, J=5.1 Hz, 2H),7.14-7.10 (m, 3H), 7.04 (d, J=8.2 Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 6.82(s, 1H), 6.27 (s, 1H), 3.89 (dd, J=5.5, 9.6 Hz, 1H), 3.76 (s, 3H), 3.34(m, 1H), 2.82 (dd, J=5.5, 14.7 Hz, 1H), 2.29 (s, 3H), 2.27 (s, 3H).

Example 66

3-[l-(4-Methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-N,N-dimethyl-2-m-tolyl-propionamide

The title compound was prepared analogously to Example 64, whereN,N-dimethylamine hydrochloride was substituted fortrans-2-aminocyclohexanol hydrochloride. HPLC: R_(t)=10.13 (Method A).MS (ES+): mass calculated for C₂₉H₃₁N₃O₂, 453.24; m/z found 454.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.22-7.08 (m, 7H), 7.06-7.03 (m, 3H),6.93 (d, J=9.0 Hz, 2H), 6.25 (s, 1H), 4.39 (dd, J=5.6, 9.0 Hz, 1H), 3.76(s, 3H), 3.35 (dd, J=8.8, 14.8 Hz, 1H), 2.95 (s, 3H), 2.81 (s, 3H), 2.80(dd, J=5.6, 14.8 Hz, 1H), 2.28 (s, 3H), 2.27 (s, 3H).

Example 67

3-[1-(4-Methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-N-methyl-2-m-tolyl-propionamide

The title compound was prepared analogously to Example 64, whereN-methylamine hydrochloride was substituted fortrans-2-aminocyclohexanol hydrochloride. HPLC: R_(t)=9.62 (Method A). MS(ES+): mass calculated for C₂₈H₂₉N₃O₂, 439.23; m/z found 440.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): 7.99 (q, J=4.7 Hz, 1H), 7.20-7.18 (m, 3H),7.14-7.09 (m, 4H), 7.04-7.01 (m, 3H), 6.93 (d, J=9.0 Hz, 2H), 6.22 (s,1H), 3.85 (dd, J=5.8, 9.4 Hz, 1H), 3.76 (s, 3H), 3.35 (dd, J=9.4, 14.6Hz, 1H), 2.86 (dd, J=5.7, 14.6 Hz, 1H), 2.54(s, 1.5 H), 2.53 (s, 1.5 H),2.329 (s, 3H), 2.27 (s, 3H).

Example 68

3-[1-(4-Methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-1-(4-methyl-piperazin-1-yl)-2-m-tolyl-propan-1-one

The title compound was prepared analogously to Example 64, whereN-methyl piperazine was substituted for trans-2-aminocyclohexanolhydrochloride. HPLC: R_(t)=8.37 (Method A). MS (ES+): mass calculatedfor C₃₂H₃₆N₄O₂, 508.28; m/z found 509.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): 7.24-7.17 (m, 3H), 7.14-7.11 (m, 4H), 7.07 (d, J=7.6 Hz, 1H),7.04 (d, J=8.2 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 6.27 (s, 1H), 4.53 (dd,J=5.8, 8.8 Hz, 1H), 3.76 (s, 3H), 3.39 (dd, J=8.9, 15.0 Hz, 1H), 3.05(br s, 4H), 2.90 (br s, 4H), 2.87 (dd, J=5.6, 15.0 Hz, 1H), 2.54 (s,3H), 2.29 (s, 3H), 2.27 (s, 3H).

Example 69

3-[1-(4-Methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3-yl]-propionicacid methyl ester

A. [1-(2-Trimethylsilanyl-ethoxymethyl)-1H-indol-3yl]-acetic acid methylester. To a suspension of sodium hydride (326 mg, 8.10 mmol) in DMF (13mL) at 0° C. was added a solution of (1H-Indol-3-yl)-acetic acid methylester (1.0 g, 5.3 mmol) in DMSO (3 mL). The mixture was stirred at 0° C.for 30 min and then at rt for 1 h. The reaction mixture was cooled backdown to 0° C., and SEMCl (1.35 mL, 8.41 mmol) was added neat. Thereaction mixture was stirred at 0° C. for 15 min and then at rt for 1 h.The reaction mixture was then partitioned between water (200 mL) anddiethyl ether (200 mL) followed by further extraction of the water layerwith ether (2×200 mL) and drying of the combined organic layers withNa₂SO₄. After removal of the solvent under reduced pressure, the crudematerial was purified by flash chromatography (EtOAc/hexanes) giving 1.1g (70%) of [1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3yl]-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃): 7.65 (d, J=7.8 Hz, 1H), 7.46(d, J=8.1, 1H), 7.26 (m, 1H), 7.22 (m, 2H), 5.51 (s, 2H), 3.83 (s, 2H),3.76 (s, 3H), 3.53 (t, J=7.9 Hz, 2H), 0.94 (t, J=7.9 Hz, 2H), 0.0 (s,9H).

B.3-[1-(4-Methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3-yl]-propionicacid methyl ester. The title compound was synthesized via Method 2 from[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3yl]-acetic acid methylester (Step A, 0.17 g, 0.56 mmol),3-bromoethyl-1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazole (Method 1pyrazole bromide, 0.10 g, 0.28 mmol), sodium hydride (22 mg, 0.56 mmol)and DMF (4.0 mL), yielding 140 mg (84%) of3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3-yl]-propionicacid methyl ester. HPLC: R_(t)=3.91 (Method B). MS (ES+): masscalculated for C₃₅H₄₁N₃O₄Si, 595.29; m/z found 596.27 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆): 7.76 (d, J=7.8 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.61(s, 1H), 7.30 (t, J=7.6 Hz, 1H), 7.27-7.19 (m, 5H), 7.15 (d, J=8.1 Hz,2H), 7.05 (d, J=9.0 Hz, 2H), 6.44 (s, 1H), 5.64 (s, 2H), 4.47 (t, J=7.6Hz, 1H), 3.89 (s, 3H), 3.71 (s, 3H), 3.62-3.52 (m, 3H), 3.25 (dd, J=6.6,14.9 Hz ,1H), 2.40 (s, 3H), 0.87 (t, J=8.0 Hz, 2H), 0.0 (s, 9H).

Example 70

3-[1-(4-Methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3-yl]-propionicacid

The title compound was synthesized by Method 2 from3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3-yl]-propionicacid methyl ester (Example 69, 0.19 g, 0.32 mmol), lithium hydroxide (40mg, 0.96 mmol), THF (1.25 mL), water (0.43 mL) and MeOH (0.43 mL),giving 167 mg (89%) of3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3-yl]-propionicacid. HPLC: R_(t)=3.66 (Method B). MS (ES+): mass calculated forC₃₄H₃₉N₃O₄Si, 581.27; m/z found 582.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):7.64 (d, J=8.2 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.45 (s, 1H), 7.19-7.04(m, 6H), 7.01 (d, J=8.2 Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 6.33 (s, 1H),5.52 (s, 2H), 4.21 (m, 1H), 3.76 (s, 3H), 3.41 (m, 2H), 3.07 (dd, J=6.3,14.3 Hz, 1H), 2.27 (s, 3H), 0.75 (t, J=8.0 Hz, 2H), 0.00 (s, 9H).

Example 71

2-(1H-Indol-3-yl)-3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-propionicacid

A solution of3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3-yl]-propionicacid (Example 70, 0.17 g, 0.29 mmol) and 1.0 M TBAF (2.88 mL) in THF washeated to 60° C. for24 h. The reaction mixture was cooled to rt, dilutedwith EtOAc (100 mL), and washed with water (3×30 mL) and brine (1×30mL). The organic layer was dried with Na₂SO₄, and the solvent wasremoved under reduced pressure. The crude residue was purified byreversed-phase HPLC giving 111 mg (85%) of2-(1H-indol-3-yl)-3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-propionicacid. HPLC: R_(t)=3.0 (Method B). MS (ES+): mass calculated forC₂₈H₂₅N₃O₃, 451.19; m/z found 452.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):10.97 (s, 1H), 7.64 (d, J=6.3 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.31 (d,J=2.4 Hz, 1H), 7.13-7.07 (m, 5H), 7.04 (d, J=8.1 Hz, 2H), 6.98 (t, J=8.0Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 6.36 (s, 1H), 4.22 (dd, J=6.1, 9.0 Hz,1H), 3.77 (s, 3H), 3.45 (dd, J=9.0, 14.7 Hz, 1H), 3.06 (dd, J=6.2, 14.7Hz, 1H), 2.27 (s, 3H).

Example 72

3-[1-(4-Methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-(1-methyl-1H-indol-3-yl)-propionicacid

A. (1-Methyl-1H-indol-3-yl)-acetic acid methyl ester. To a suspension ofsodium hydride (104 mg, 7.61 mmol) in DMF (11 mL) was added a solutionof 1H-indol-3-yl-acetic acid methyl ester (0.50 g, 2.6 mmol) in DMF (5.0mL). The mixture was stirred for 1 h followed by addition of methyliodide (1.1 g, 7.8 mmol). The reaction mixture was stirred for anadditional 18 h, quenched, diluted with saturated ammonium chloride (200mL), and then extracted with diethyl ether (3×100 mL). The combinedorganic layers were dried with Na₂SO₄, and the solvent was removed underreduced pressure. The crude residue was purified by flash chromatography(EtOAc/hexanes) giving 100 mg (19%) of (1-methyl-1H-indol-3-yl)-aceticacid methyl ester after purification. HPLC: R_(t)=8.91 (Method A). MS(ES+): mass calculated for C₁₂H₁₃NO₂, 203.09; m/z found 204.09 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.60 (d, J=7.9 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H),7.23 (t, J=8.2 Hz, 1H), 7.13 (t, 7.4 Hz, 1H), 7.04 (s, 1H), 3.77 (s,2H), 3.76 (s, 3H), 3.69 (s, 3H).

B.3-[1-(4-Methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-(1-methyl-1H-indol-3-yl)-propionicacid. The title compound was prepared by Method 2 from(1-methyl-1H-indol-3-yl)-acetic acid methyl ester (0.10 g, 0.49 mmol),3-bromoethyl-1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazole (89 mg, 0.25mmol), sodium hydride (19 mg, 0.49 mmol) and DMF (4.0 mL), giving3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-(1-methyl-1H-indol-3-yl)-propionicacid methyl ester, which was not isolated. The ester was converted tothe acid in situ by adding 2.5 mL (4.9 mmol) LiOH solution giving 57 mg(49%) of3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-(1-methyl-1H-indol-3-yl)-propionicacid. HPLC: R_(t)=3.23 (Method B). MS (ES+): mass calculated forC₂₉H₂₇N₃O₃, 465.21; m/z found 466.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):12.15 (br s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.32(s, 1H), 7.17-7.10 (m, 5H), 7.05-7.03 (m, 3H), 6.93 (d, J=8.9 Hz, 2H),6.38 (s, 1H), 4.22 (dd, J=9.1, 5.9 Hz, 1H), 3.76 (s, 6H), 3.44 dd,J=14.7, 9.2 Hz, 1H), 3.04 (dd, J=5.9, 14.7 Hz, 1H), 2.27 (s, 3H).

Example 73

3-[1-(4-Methoxy-phenyl)-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionitrile

To a solution of3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionamide(Example 65, 0.31 g, 0.73 mmol) in pyridine (0.115 mL, 1.46 mmol) anddioxane (2.0 mL) at 0° C. was added TFAA (0.11 mL, 0.80 mmol). Thesolution was stirred at 0° C. for 30 min, allowed to warm to rt andstirred for an additional 3 h. The solvent was removed under reducedpressure, and the residue was re-dissolved in EtOAc (100 mL). Thissolution was washed with water (1×50 mL) and brine (1×50 mL) and driedwith Na₂SO₄, and then solvent was removed under reduced pressure giving295 mg (>99%) of3-[1-(4-methoxy-phenyl)-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionitrile.HPLC: R_(t)=3.53 (Method B). MS (ES+): mass calculated for C₂₇H₂₅N₃O,407.20; m/z found 408.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.33-7.26 (m,3H), 7.18-7.12 (m, 5H), 7.08 (d, J=8.2 Hz, 2H), 6.95 (d, J=8.9 Hz, 2H),6.48 (s, 1H), 4.58 (dd, J=5.9, 9.6 Hz, 1H), 3.77 (s, 3H), 3.27 (dd,J=9.6, 14.6 Hz, 1H), 3.15 (dd, J=5.9, 14.6 Hz, 1H), 2.33 (s, 3H), 2.28(s, 3H).

Example 74

5-{2-1-(4-Methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-1-m-tolyl-ethyl)-1H-tetrazole

3-[1-(4-Methoxy-phenyl)-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionitrile(Example 73, 0.10 g, 0.24 mmol), sodium azide (32 mg, 0.50 mmol) andammonium chloride (26 mg, 0.50 mmol) were mixed in DMF (3.0 mL) andheated at 100° C. for 4 days. The reaction mixture was cooled, dilutedwith water (25 mL) and extracted with EtOAc (3×25 mL). The combinedorganic layers were washed with brine (1×25 mL) and dried with Na₂SO₄,and the solvent was removed under reduced pressure yielding 21 mg (20%)of5-{2-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-1-m-tolyl-ethyl}-1H-tetrazole.HPLC: R_(t)=3.16 (Method B). MS (ES+): mass calculated for C₂₇H₂₆N₆O,450.22; m/z found 451.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.25-7.17 (m,3H), 7.12 (d, J=7.9 Hz, 2H), 7.07 (d, J=7.4 Hz, 1H), 7.04 (d, J=9.0 Hz,2H), 6.99(d, J=8.1 Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 6.23 (s, 1H), 4.85(dd, J=6.7, 9.2 Hz, 1H), 3.75 (s, 3H), 3.60 (dd, J=9.3, 14.8 Hz, 1H),3.34 (dd, J=6.4, 14.4 Hz, 1H), 2.28 (s, 3H), 2.26 (s, 3H).

Example 75

(E)-3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-acrylicacid

A.5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole-3-carbaldehyde.To a stirred solution of[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-methanol(Example 1 Step C, 1.0 g, 2.9 mmol) in CH₂Cl₂ (13 mL) under N₂ was addedDess-Martin periodinane (2.1 g, 4.9 mmol) at rt. After 3 h, Na₂S₂O₃ (5.0g, 20 mmol) dissolved in saturated NaHCO₃ (25 mL) and EtOAc (25 mL) wereadded, and the mixture was stirred until the layers were clear. Thelayers were separated, and the aqueous phase was extracted with EtOAc(3×15 mL). The combined organic extracts were dried over Na₂SO₄ andfiltered, and the solvent was removed under reduced pressure to afford0.95 g (96%) of the crude aldehyde, which was used without furtherpurification. HPLC: R_(t)=10.3 (Method A). ¹H NMR (400 MHz, CDCl₃): 9.98(s, 1H), 7.32 (s, 1H), 7.30 (d, J=2.3 Hz, 1H), 7.19-7.16 (m, 2H), 6.95(s, 1H), 6.91 (dd, J=8.1, 2.3 Hz, 1H), 6.88-6.84 (m, 2H), 3.78 (s, 3H).

B.3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-acrylicacid ethyl ester. To a stirred solution containing sodium hydride (0.20mg, 60% in mineral oil, 4.8 mmol) suspended in EtOH (5 mL) was addedethyl-m-tolyacetate (0.87 g, 4.9 mmol) at rt. After 30 min,5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole-3-carbaldehyde(Step A, 0.562 g, 1.63 mmol) in 2 mL DMF was added. The reaction mixturewas stirred for 18 h at 70° C. The solvent was removed under reducedpressure, and the residue was purified by silica gel chromatography with7:93 MeOH/CH₂Cl₂ to afford 220 mg (27.2%) of3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-acrylicacid ethyl ester. HPLC: R_(t)=11.76 (Method A). MS (ES+): masscalculated for C₂₈H₂₄Cl₂N₂O3, 506.12; m/z found 507.0 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.83-7.80 (m, 1H), 7.74-7.71 (m, 2H), 7.37-7.35 (m,1H), 7.33-7.29 (m, 4H), 7.19 (d, J=4.5 Hz, 2H), 6.92-6.88 (m, 2H), 4.19(dd, J=13.9, 7.2 Hz, 2H), 3.78 (s, 3H), 2.51 (s, 3H), 1.21 (t, J=6.8,Hz, 3H).

C.3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-acrylicacid. To a stirred solution containing3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1-H-pyrazol-3-yl]-2-m-tolyl-acrylicacid ethyl ester (Step B, 50 mg, 0.10 mmol) was added 2 mL LiOH (2 M).After 4 h at 50° C., the solvent was removed under reduced pressure andthe residue was purified by silica gel chromatography with 5:95MeOH/CH₂Cl₂ to afford 34 mg (72.3%) of the title compound. HPLC:R_(t)=10.65 (Method A). MS (ES+): mass calculated for C₂₆H₂₀Cl₂N₂O₃,478.09; m/z found 479.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.35 (t, J=8.0Hz, 1H), 7.28-7.23 (m, 3H), 7.15-7.11 (m, 3H), 7.09 (d, J=2.0 Hz, 1H),6.88-6.86 (m, 2H), 6.77 (dd, J=8.3, 2.0 Hz, 1H), 5.45 (s, 1H), 3.82 (s,3H), 2.39 (s, 3H).

Example 76

3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-methyl-2-m-tolyl-propionicacid

A.3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-methyl-2-m-tolyl-propionicacid ethyl ester. To a solution of3-(5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid ethyl ester (Method 2, product from alkylation step beforehydrolysis) (50 mg, 0.10 mmol) in THF (1.0 mL) at 0° C. was added a 1.0M solution of NaHMDS (0.15 mL, 0.15 mmol). The solution was stirred at0° C. for 2 h, then iodomethane (41 mg, 0.29 mmol) was added neat. Afterstirring for 1 h the reaction was quenched with saturated ammoniumchloride (50 mL), and the reaction mixture was extracted with EtOAc(3×50 mL). The combined organic layers were washed with brine (1×50 mL)and dried with Na₂SO₄, and the solvent was removed under reducedpressure. The crude material was purified by flash chromatography(EtOAc/hexanes) giving 31 mg (60%) of3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-methyl-2-m-tolyl-propionicacid ethyl ester. HPLC: R_(t)=3.79 (Method B). MS (ES+): mass calculatedfor C₂₉H₂₈Cl₂N₂O₃, 522.15; m/z found 523.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): 7.58 (d, J=8.4 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.25 (t, J=7.6Hz, 1H), 77.17-7.14 (m, 4H), 7.08 (d, J=7.4 Hz, 1H), 7.05 (dd, J=2.0 Hz,8.3 Hz, 1H), 6.97 (d, J=8.9 Hz, 2H), 6.22 (s, 1H), 4.10 (m, 2H), 3.77(s, 3H), 3.40 (d, J=13.9 Hz, 1H), 3.17 (d, J=13.9 Hz, 1H), 2.13 (s, 3H),1.49 (s, 3H), 1.12 (t, J=7.1 Hz, 3H).

B.3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-methyl-2-m-tolyl-propionicacid. The title compound was prepared by Method 2 from3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-methyl-2-m-tolyl-propionicacid ethyl ester (0.11 g, 0.21 mmol), lithium hydroxide (88 mg, 2.1mmol), THF (2.3 mL), MeOH (0.87 mL) and water (0.87 mL) giving 93 mg(90%) of3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-methyl-2-m-tolyl-propionicacid. HPLC: R_(t)=3.42 (Method B). MS (ES+): mass calculated forC₂₇H₂₄Cl₂N₂O₃, 494.12; m/z found 495.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): 12.50 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H),7.26-7.19 (m, 3H), 7.16 (d, J=9.0 Hz, 2H), 7.08 (d, J=7.1 Hz, 1H), 7.03(dd, J=2.0 Hz, 8.4 Hz, 1H), 6.97 (d, J=9.0 Hz, 2H), 6.20 (s, 1H), 3.78(s, 3H), 3.37 (d, J=14.0 Hz, 1H), 3.14 (d, J=14.0 Hz, 1H), 2.31 (s, 3H),1.46 (s, 3H).

Example 77

3-[5-(4-Bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

A. 2-m-Tolyl-5-trimethylsilanyl-pent-4-ynoic acid ethyl ester. To a −78°C. solution of m-tolyl-acetic acid ethyl ester (2.0 g, 11 mmol) in THF(37 mL), a 2.0 M solution of lithium diisopropylamine in THF (5.6 mL, 11mmol) was added dropwise. The mixture was stirred at −78° C. for 1 h andthen added to a −78° C. solution of propargyl bromide (5.6 mL, 11 mmol,1 equiv) in THF (30 mL). The reaction mixture was allowed to warm toroom temperature and stirred for 12 h. Diethyl ether (40 mL) and satd aqNH₄Cl (50 mL) were added, and the resulting aqueous layer wasback-extracted with Et₂O (2×50 mL). The combined organic layers werewashed with 1N HCl (50 mL) then brine (50 mL), and dried (MgSO₄). Thesolvent was evaporated under reduced pressure, and the residue waspurified by chromatography (silica gel, 20% ethyl acetate/hexanes) toafford the desired silanyl-pentynoic acid ester (2.90 g, 90% yield). TLC(silica gel, 1:9 EtOAc/hexanes): R_(f)=0.54. MS (ESI): mass calculatedfor C₁₇H₂₄O₂Si, 288.15; m/z found, 289.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.17-6.96 (m, 4H), 4-13-3.99 (m, 2H), 3.65-3.62 (m, 1H), 2.82(dd, J=16.8, 8.4 Hz, 1H), 2.54 (d, J=16.8, 7.0 Hz, 1H), 2.23 (s, 3H),1.13 (t, J=10.0 Hz, 3H), 0.00 (s, 9H).

B. 6-(4-Bromo-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acid ethyl ester. To a0° C. solution of 2-m-tolyl-5-trimethylsilanyl-pent-4-ynoic acidethylester (9.5 g, 33 mmol) and 4-bromobenzoyl chloride (9.4 g, 43 mmol,1.3 equiv) in CH₂Cl₂ (550 mL) was added aluminum chloride (9.5 g, 50mmol, 1.5 equiv) portionwise. The mixture was stirred at 0° C. for 2 h,then the reaction was quenched with satd aq potassium sodium tartrate(200 mL). The resulting mixture was stirred at room temperature for 2 h.The layers were separated, and the aqueous layer was back-extracted withCH₂Cl₂ (3×150 mL). The combined organic layers were washed with 1N NaOH(70 mL) then brine (70 mL), and dried (MgSO₄). The solvent wasevaporated under reduced pressure, and the residue was purified bychromatography (silica gel, 25% ethyl acetate/hexanes) to afford thedesired benzoyl-pentynoic acid ester (9.2 g, 70%). TLC (silica gel, 1:9EtOAc/hexanes): R_(f)=0.28. MS (ESI): mass calculated for C₂₁H₁₉BrO₃,398.05; m/z found, 399/400 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.14 (d,J=8.9 Hz, 2H), 7.14 (d, J=8.9 Hz, 2H), 7.29-7.14 (m, 3H), 4.23-4.12 (m,2H), 3.88 (t, J=7.8 Hz, 1H), 3.09 (dAB syst., J=17.3, 7.8 Hz, 2H), 2.38(s, 3H), 1.24 (t, J=9.2 Hz, 3H).

C. 3-[5-(4-Bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid ethyl ester. To a solution of6-(4-bromo-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acid ethyl ester (7.5 g,19 mmol) in THF (40 mL) was added hydrazine (4.5 g, 28 mmol, 1.5 equiv)and Cs₂CO₃ (9.0 g, 28 mmol, 1.5 equiv). The reaction mixture was stirredat room temperature for 12 h. The resulting mixture was diluted withethyl acetate (30 mL), and a satd aq solution of cesium carbonate (50mL) was added. The resulting aqueous layer was back-extracted with ethylacetate (2×30 mL). The combined organic layers were washed with satd aqNaHCO₃ (50 mL) then brine (50 mL), and dried (MgSO₄). The solvent wasevaporated under reduced pressure, and the residue was purified bychromatography (silica gel, 25% ethyl acetate/hexanes) to afford thedesired compound (5.5 g, 58%). TLC (silica gel, 3:7 EtOAc/hexanes):R_(f)=0.35. MS (ESI): mass calculated for C₂₈H₂₇BrN₂O₂, 502.13; m/zfound, 503/505 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.39 (d, J=10.7 Hz, 2H),7.25-7.01 (m, 10H), 6.17 (s, 1H), 4.19-4.03 (m, 3H), 3.52 (dd, J=14.7,9.6 Hz, 1H), 3.09 (dd, J=14.7, 6.0, 1H), 2.35 (s, 6H), 1.19 (t, J=7.1Hz, 3H).

D. 3-[5-(4-Bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid. To a solution of3-[5-(4-bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid ethyl ester (100 mg, 0.2 mmol) was added LiOH (14 mg, 0.6 mmol, 3equiv) in 2:1 THF/H₂O (1 mL). After 3 h at 45° C., the mixture waspurified by preparative reversed-phase HPLC (acetonitrile/water) toafford the title compound (66 mg, 79 %). HPLC: R_(t)=4.25 (Method A). MS(ESI): mass calculated for C₂₆H₂₃BrN₂O₂, 474.09; m/z found, 475/477[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.40 (d, J=8.5 Hz, 2H), 7.22 (d, J=7.6Hz, 2H), 7.19-7.05 (m, 7H), 7.01 (d, J=8.5 Hz, 2H), 6.23 (s, 1H), 4.10(dd, J=9.6, 5.5 Hz, 1H), 3.53 (dd, J=14.8, 9.6 Hz, 1H), 3.13 (dd,J=14.8, 5.5 Hz, 1H), 2.36 (s, 3H), 2.34 (s, 3H).

The compounds of Examples 78-93 were made according to the syntheticmethods outlined in Example 77 and Scheme L.

Example 78

3-[5-(4-Dimethylamino-phenyl)-1-pyridin-2-yl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

HPLC: R_(t)=3.90 (Method B). MS (ESI): mass calculated for C₂₆H₂₆N₄O₂,426.21; m/z found, 427.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.38 (d, J=6.3Hz, 1H), 7.76 (td, J=7.4, 1.2 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.24-7.18(m, 4H), 7.11-7.07 (m, 3H), 6.22 (s, 1H), 4.14 (dd, J=9.6, 5.5 Hz, 1H),3.56 (dd, J=15.0, 9.6 Hz, 1H), 3.12 (dd, J=15.0, 5.5 Hz, 1H), 3.08, (s,6H), 2.34 (s, 3H).

Example 79

3-(5-Naphthalen-1-yl-2-pyridin-2-yl-2H-pyrazol-3-yl)-2-m-tolyl-propionicacid

HPLC: R_(t)=3.36 (Method B). MS (ESI): mass calculated for C₂₈H₂₃N₃O₂,433.18; m/z found, 434.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.44 (d, J=4.9Hz, 1H), 8.25 (s, 1H), 8.09 (d, J=8.2 Hz, 1H), 8.03 (d, J=8.5 Hz, 1H),7.89-7.82 (m, 4H), 7.50-7.46 (m, 2H), 7.28-7.18 (m, 4H), 7.09 (d, J=6.8Hz, 1H), 6.64 (s, 1H), 4.34 (dd, J=9.0, 5.7 Hz, 1H), 3.94 (dd, J=14.8,9.0 Hz, 1H), 3.66 (dd, J=14.8, 5.7 Hz, 1H), 2.34 (s, 3H).

Example 80

3-[5-Naphthalen-2-yl-1-(5-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

HPLC: R_(t)=3.41 (Method B). MS (ESI): mass calculated for C₂₉H₂₂F₃N₃O₂,501.17; m/z found, 520/522 [M+H₃O]⁺. ¹H NMR (500 MHz, CDCl₃): 8.45 (s,1H), 7.89-7.74 (m, 6H), 7.66 (d, J=8.5 Hz, 1H), 7.54-7.48 (m, 2H),7.28-7.19 (m, 3H), 7.12-7.11 (m, 1H), 6.33 (s, 1H), 4.16 (dd, J=9.6, 5.7Hz, 1H), 3.60 (dd, J=15.0, 9.6 Hz, 1H), 3.15 (dd, J=15.0, 5.7 Hz, 1H),2.35 (s, 3H).

Example 81

3-[5-(2-Chloro-pyridin-3-yl)-1-(2,4-dichloro-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

MS (ESI): mass calculated for C₂₄H₁₈Cl₃N₃O₂, 485.05; m/z found, 486/488[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.38 (d, J=2.0 Hz, 1H), 7.70-7.67 (m,2H), 7.59-7.53 (m, 2H), 7.25-7.19 (m, 2H), 7.13 (s, 1H), 7.04 (d, J=8.8Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.04 (s, 1H), 3.95 (dd, J=7.0, 4.6 Hz,1H), 3.62 (dd, J=17.0, 4.6 Hz, 1H), 3.00 (dd, J=17.0, 7.0 Hz, 1H), 2.34(s, 1H).

Example 82

3-(5-Benzo[1,3]dioxol-5-yl-2-cyclohexylmethyl-2H-pyrazol-3-yl)-2-m-tolyl-propionicacid

MS (ESI): mass calculated for C₂₇H₃₀N₂O₄, 446.22; m/z found, 447.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.30-7.25 (m, 2H), 7.21-7.20 (m, 2H),7.16-7.15 (m, 2H), 6.82 (d, J=8.2 Hz, 1H), 6.22 (s, 1H), 3.96-3.86 (m,3H), 3.43 (dd, J=16.0, 9.3 Hz, 1H), 2.99 (dd, J=16.0, 5.7 Hz, 1H), 2.36(s, 3H),1.72-1.53 (m, 5H), 1.21-1.12 (m, 3H), 0.98-0.92 (m, 2H).

Example 83

3-(2-Benzyl-5-naphthalen-2-yl-2H-pyrazol-3-yl)-2-m-tolyl-propionic acid

MS (ESI): mass calculated for C₃₀H₂₆N₂O₂, 446.20; m/z found, 447.8[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.17 (s, 1H), 7.84-7.78 (m, 4H),7.46-7.44 (m, 2H), 7.29-7.24 (m, 3H), 7.18 (t, J=7.6 Hz, 1H), 7.09-7.06(m, 3H), 7.01-6.99 (m, 2H), 6.47 (s, 1H), 5.36 (AB syst., Jab=16 Hz,2H), 3.74 (dd, J=8.7, 6.3 Hz, 1H), 3.39 (dd, J=15.0, 8.7 Hz, 1H), 2.92(dd, J=15.0, 6.3 Hz, 1H), 2.29 (s, 3H).

Example 84

3-[2-Benzyl-5-(4-dimethylamino-phenyl)-2H-pyrazol-3-yl]-2-m-tolyl-propionicacid

MS (ESI): mass calculated for C₂₈H₂₉N₃O₂, 439.23; m/z found, 440.7[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.38 (d, J=8.5 Hz, 2H), 7.31-7.25 (m,5H), 7.20 (t, J=8.0 Hz, 1H), 7.10-7.06 (m, 3H), 7.01-7.00 (m, 2H), 6.37(s, 1H), 5.33 (AB syst., Jab=16.0 Hz, 2H), 3.73 (dd, J=9.2, 5.7 Hz, 1H),3.38 (dd, J=15.7, 9.2 Hz, 1H), 3.13 (s, 6H), 2.88 (dd, J=15.4, 5.7 Hz,1H), 2.31 (s, 3H).

Example 85

3-[5-(4-Bromo-2-chloro-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

HPLC: R_(t)=4.30 (Method A). MS (ESI): mass calculated forC₂₆H₂₂BrClN₂O₂, 508.06; m/z found, 509/511 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 7.53 (d, J=1.9 Hz, 1H), 7.32 (dd, J=8.2, 1.9 Hz, 1H), 7.22 (t,J=7.4 Hz, 1H), 7.17-7.15 (m, 2H), 7.11-7.06 (m, 3H), 7.03-6.98 (m, 3H),6.20 (s, 1H), 4.08 (dd, J=9.0, 6.3 Hz, 1H), 3.55 (dd, J=14.8, 9.0 Hz,1H), 3.18 (dd, J=14.8, 6.3 Hz, 1H), 2.34 (s, 3H), 2.31 (s, 3H).

Example 86

3-[5-(4-Dimethylamino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

HPLC: R_(t)=1.26 (Method H). MS (ESI): mass calculated for C₂₈H₂₉N₃O₂,439.23; m/z found, 440.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.30 (s, 3H),7.24-7.20 (m, 3H), 7.13-7.07 (m, 2H), 6.97 (d, J=8.3 Hz, 2H), 6.67 (d,J=8.3 Hz, 2H), 6.13 (s, 1H), 4.01 (dd, J=9.3, 6.1 Hz, 1H), 3.50 (dd,J=14.9, 9.3 Hz, 1H), 3.07 (dd, J=14.9, 6.1 Hz, 1H), 2.36 (s, 3H), 2.34(s, 3H).

Example 87

3-[5-(1-Methyl-2,3-dihydro-1H-indol-5-yl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

HPLC: R_(t)=3.71 (Method A). MS (ESI): mass calculated for C₂₉H₂₉N₃O₂,451.23; m/z found, 452.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.26-7.10 (m,8H), 6.94-6.89 (m, 2H), 6.56 (d, J=8.2 Hz, 1H), 6.20 (s, 1H), 4.13 (dd,J=9.6, 5.5 Hz, 1H), 3.54 (dd, J=14.8, 9.6 Hz, 1H), 3.48 (t, J=8.2 Hz,2H), 3.13 (dd, J=14.8, 5.5 Hz, 1H), 2.96 (t, J=8.2 Hz, 2H), 2.85 (s,3H), 2.34 (s, 3H).

Example 88

3-(5-Naphthalen-2-yl-2-pyridin-4-ylmethyl-2H-pyrazol-3-yl)-2-m-tolyl-propionicacid

MS (ESI): mass calculated for C₂₉H₂₅N₃O₂, 447.19; m/z found, 448.3[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.56-8.55 (m, 2H), 8.17 (s, 1H),7.86-7.78 (m, 4H), 7.48-7.44 (m, 2H), 7.32-7.31 (m, 2H), 7.17 (t, J=7.8Hz, 1H), 7.07-7.04 (m, 3H), 6.70 (s, 1H), 5.52 (AB syst., Jab=17.9 Hz,2H), 3.97 (dd, J=:9.8, 4.8 Hz, 1H), 3.31 (dd, J=15.0, 9.8 Hz, 1H), 2.92(dd, J=15.0, 4.8 Hz, 1H), 2.27 (s, 3H).

Example 89

3-(5-Naphthalen-2-yl-1-pyridin-4-ylmethyl-1H-pyrazol-3-yl)-2-m-tolyl-propionicacid

MS (ESI): mass calculated for C₂₉H₂₅N₃O₂, 447.19; m/z found, 448.3[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.65-8.64 (m, 2H), 7.89-7.86 (m, 2H),7.80-7.70 (m, 1H), 7.70 (s, 1H), 7.56-7.52 (m, 2H), 7.30-7.19 (m, 6H),7.13-7.11 (m, 2H), 6.36 (s, 1H), 5.51 (s, 1H), 4.13 (dd, J=10.1, 5.0 Hz,1H), 3.55 (dd, J=14.6, 10.1 Hz, 1H), 3.38 (s, 1H), 3.10 (dd, J=14.6, 5.0Hz, 1H), 2.33 (s, 3H).

Example 90

3-[5-(3-Dimethylamino-phenyl)-2-p-tolyl-2H-pyrazol-3-yl]-2-m-tolyl-propionicacid

HPLC: R_(t)=3.16 (Method A). MS (ESI): mass calculated for C₂₈H₂₉N₃O₂,439.23; m/z found, 440.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.64 (t, J=1.7Hz, 1H), 7.50 (d, J=7.7 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.28-7.24 (m,4H), 7.19-7.12 (m, 2H), 7.07-7.05 (m, 1H), 7.01-7.00 (m, 2H), 3.83 (dd,J=9.0, 6.3 Hz, 1H), 3.43 (dd, J=15.5, 9.0 Hz, 1H), 3.11 (s, 3H), 2.99(dd, J=15.5, 6.3 Hz, 1H), 2.42 (s, 3H), 2.29 (s, 3H).

Example 91

3-[5-(3-Dimethylamino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

HPLC: R_(t)=3.48 (Method A). MS (ESI): mass calculated for C₂₈H₂₉N₃O₂,439.23; m/z found, 440.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.36-7.33 (m,2H), 7.23-7.19 (m, 3H), 7.15-7.09 (m, 7H), 6.36 (s, 1H), 4.10 (dd,J=9.9, 5.4 Hz, 1H), 3.54 (dd, J=14.7, 9.9 Hz, 1H), 3.11 (dd, J=14.9, 5.4Hz, 1H), 2.97 (s, 6H), 2.34 (s, 6H).

Example 92

(S)-3-(5-Naphthalen-2-yl-1-pyridin-2-yl-1H-pyrazol-3-yl)-2-m-tolyl-propionicacid

HPLC: R_(t)=5.95 (Method J). MS (ESI): mass calculated for C₂₈H₂₃N₃O₂,433.18; m/z found, 434.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.81-7.74 (m,5H), 5.52-7.50 (m, 2H), 7.26-7.09 (m, 7H), 6.39 (s, 1H), 4.18 (dd,J=10.2, 4.9 Hz, 1H), 3.62 (dd, J=14.8, 10.2 Hz, 1H), 3.12 (dd, J=14.8,4.9 Hz, 1H), 2.34 (s, 3H).

Example 93

(R)-3-(5-Naphthalen-2-yl-1-pyridin-2-yl-1H-pyrazol-3-yl)-2-m-tolyl-propionicacid

HPLC: R_(t)=3.95 (Method J). MS (ESI): mass calculated for C₂₈H₂₃N₃O₂,433.18; m/z found, 434.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.81-7.74 (m,5H), 5.52-7.50 (m, 2H), 7.26-7.09 (m, 7H), 6.39 (s, 1H), 4.18 (dd,J=10.2, 4.9 Hz, 1H), 3.62 (dd, J=14.8, 10.2 Hz, 1H), 3.12 (dd, J=14.8,4.9 Hz, 1H), 2.34 (s, 3H).

Example 94

(Amination)

3-[5-(4-Allylamino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

A.3-[5-(4-Allylamino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid ethyl ester. To a mixture of Pd₂(dibenzylideneacetone)₃ (4 mg,0.004 mmol, 1 mol %), 2-(di-tert-butylphosphino)biphenyl (6 mg, 0.02mmol, 5 mol %) and K₃PO₄ (130 mg, 0.61 mmol, 1.5 equiv) was added asolution of3-[5-(4-bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid ethyl ester (Example 77, Step C; 200 mg, 0.4 mmol) in toluene (0.6mL) followed by allylamine (0.030 mL, 0.48 mmol, 1.2 equiv). Theresulting mixture was stirred at 110° C. for 12 h and then cooled toroom temperature. Ethyl acetate (2 mL) and water (3 mL) were added, andthe resulting aqueous layer was back-extracted with EtOAc (3×2 mL). Thecombined organic layers were washed with brine (3 mL), and then dried(MgSO₄). The solvent was evaporated under reduced pressure, and theresidue was purified by chromatography (silica gel, 25% ethylacetate/hexanes) to afford the desired compound (90 mg, 47%). HPLC:R_(t)=3.19 (Method B). MS (ESI): mass calculated for C₃₁H₃₃N₃O₂, 479.26;m/z found, 480.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.29 (s, 1H),7.27-7.04 (m, 7H), 6.96 (d, J=8.5 Hz, 2H), 6.49 (d, J=8.5 Hz, 2H), 6.07(s, 1H), 5.96-5.89 (m, 1H), 5.29-5.25 (m, 1H), 5.18-5.16 (m, 1H),4.20-4.14 (m, 1H), 4.10-4.02 (m, 2H), 3.76-3.75 (m, 2H), 3.52-3.45 (m,1H), 3.08 (dd, J=14.5, 6.0 Hz, 1H), 2.34 (s, 6H), 1.19 (t, J=7.1 Hz,1H).

B.3-[5-(4-Allylamino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid. To a solution of3-[5-(4-allylamino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid ethyl ester (90 mg, 0.2 mmol) was added LiOH (14 mg, 0.58 mmol, 3equiv) in 2:1 THF/H₂O (1 mL). After 3 h at 45° C., the mixture waspurified by preparative reversed-phase HPLC (acetonitrile/water) toafford the desired compound (70 mg, 77 %). MS (ESI): mass calculated forC₂₉H₂₉N₃O₂, 451.23; m/z found, 452.6 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.21-7.03 (m, 8H), 6.93 (d, J=8.8, 2H), 6.26 (s, 1H), 5.88-5.83 (m, 1H),5.29-5.24 (m, 2H), 4.06 (dd, J=10.4, 5.1 Hz, 1H), 3.79(d, J=6.3 Hz, 2H),3.54 (dd, J=15.0, 10.4 Hz, 1H), 3.09 (dd, J=15.0 5.1 Hz, 1H), 2.33 (s,3H), 2.32 (s, 3H).

The compounds of Examples 95-101 were made according to the syntheticmethods outlined in Example 94 and Scheme L.

Example 95

3-[5-(2-Chloro-4-pyrrolidin-1-yl-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

HPLC: R_(t)=4.35 (Method A). MS (ESI): mass calculated for C₃₀H₃₀ClN₃O₂,499.20; m/z found, 500.10 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.23-7.15 (m,3H), 7.10-7.05 (m 5H), 6.89 (d, J=8.8 Hz, 1), 6.49 (d, J=2.5 Hz, 1H),6.32 (dd, J=8.8, 2.5 Hz, 1H), 6.15 (s, 1H), 4.12 (d, J=9.0, 6.0 Hz, 1H),3.55 (dd, J=14.8, 9.0 Hz, 1H), 3.26-3.24 (m, 4H), 3.18 (dd, J=14.8, 6.0Hz, 1H), 2.33 (s, 3H), 2.30 (s, 3H), 2.07-1.99 (m, 4H).

Example 96

3-[5-(4-Diethylamino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

HPLC: R_(t)=3.21 (Method A). MS (ESI): mass calculated for C₃₀H₃₃N₃O₂,467.26; m/z found, 468.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.26-7.16 (m,8H), 7.09-7.08 (m, 4H), 6.22 (s, 1H), 4.08 (dd, J=9.3, 6.0 Hz, 1H), 3.52(dd, J=14.8, 9.3 Hz, 1H), 3.44 (q, J=7.1 Hz, 4H), 3.11 (dd, J=14.8 6.0Hz, 1H), 2.34 (s, 3H), 2.32 (s, 3H), 1.09 (t, J=7.1 Hz).

Example 97

3-[5-(4-Isobutylamino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

HPLC: R_(t)=4.02 (Method A). MS (ESI): mass calculated for C₃₀H₃₃N₃O₂,467.26; m/z found, 468.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.20-6.99 (m,8H), 6.98 (d, J=8.8 Hz, 2H), 6.81 (d, J=8.5 Hz, 2H), 6.17 (s, 1H), 4.07(dd, J=9.9, 5.5 Hz, 1H), 3.52 (dd, J=14.8, 9.9 Hz, 1H), 3.08 (dd,J=14.8, 5.5 Hz, 1H), 2.96 (d, J=7.1 Hz, 2H), 2.32 (s, 3H), 2.31 (s, 3H),1.95-1.92 (m, 1H), 0.96 (d J=6.5 Hz, 6H).

Example 98

3-[5-(4-Morpholin-4-yl-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

HPLC: R_(t)=3.86 (Method A). MS (ESI): mass calculated for C₃₀H₃₁N₃O₃,481.24; m/z found, 482.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.21-7.09 (m,8H), 7.07 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 6.21 (s, 1H), 4.08(dd, J=9.3, 5.8 Hz, 1H), 3.89-3.87 (m, 4H), 3.54 (dd, J=14.8, 9.3 Hz,1H), 3.23-3.22 (m, 4H), 3.13 (dd, J=14.8, 5.8 Hz, 1H), 2.35 (s, 3H),2.33 (s, 3H).

Example 99

3-{5-[2-Chloro-4-(ethyl-methyl-amino)-phenyl]-1-p-tolyl-1H-pyrazol-3-yl}-2-m-tolyl-propionicacid

HPLC: R_(t)=4.13 (Method A). MS (ESI): mass calculated for C₂₉H₃₀ClN₃O₂,487.20; m/z found, 488.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.24-7.15 (m,3H), 7.10-7.07 (m, 5H), 6.96 (d. J=8.7 Hz, 1H), 6.77 (d, J=2.4 Hz, 1H),6.62 (dd, J=8.7, 2.4 Hz, 1H), 6.19 (s, 1H), 4.12 (dd, J=9.3, 6.0 Hz,1H), 3.56 (dd, J=14.8, 9.3 Hz, 1H), 3.39 (q, J=7.1 Hz, 2H), 3.18 (dd,14.8, 6.0 Hz, 1H), 2.94 (s, 3H), 2.34 (s, 3H), 2.31 (s, 3H), 1.13 (t,J=7.1 Hz, 3H).

Example 100

3-{5-[4-(Ethyl-methyl-amino)-phenyl]-1-p-tolyl-1H-pyrazol-3-yl}-2-m-tolyl-propionicacid

HPLC: R_(t)=3.29 (Method A). MS (ESI): mass calculated for C₂₉H₃₁N₃O₂,453.24; m/z found, 454.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.26-7.08 (m,12H), 6.23 (s, 1H), 4.09-4.05 (m, 1H), 3.52 (dd, J=14.9, 9.3 Hz, 1H),3.44 (q, J=7.1 Hz, 2H), 3.11 (dd, J=14.9, 6.1 Hz, 1H), 3.06 (s, 3H),2.35 (s, 3H), 2.32 (s, 3H), 1.12 (t, J=7.1 Hz, 3H).

Example 101

3-{5-[4-(Isopropyl-methyl-amino)-phenyl]-1-p-tolyl-1H-pyrazol-3-yl}-2-m-tolyl-propionicacid

HPLC: R_(t)=4.06 (Method A). MS (ESI): mass calculated for C₃₀H₃₃N₃O₂,467.26; m/z found, 468.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.34 (d, J=8.8Hz, 2H), 7.26-7.06 (m, 10H), 6.26 (s, 1H), 4.09 (dd, J=9.6, 5.9 Hz, 1H),3.81-3.78 (m, 1H), 3.53 (dd, J=14.9, 9.6 Hz, 1H), 3.12 (dd, J=14.9, 5.9Hz, 1H), 3.11 (s, 3H), 2.36 (s, 3H), 2.33 (s, 3H), 1.28 (d, J=6.6 Hz,6H).

Example 102

(Amidation)

3-[5-(4-Acetylamino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

To a solution of3-[5-(4-bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid ethyl ester (Example 77, Step C; 100 mg, 0.2 mmol) in dioxane (0.6mL) was added Cul (3 mg, 0.02 mmol, 10 mol %),(1R,2R)-N,N-dimethyl-cyclohexane-1,2-diamine (0.003 mL, 0.02 mmol, 10mol %), K₂CO₃ (55 mg, 0.40 mmol, 2.0 equiv) and N-methylformamide (15mg, 0.26 mmol, 1.3 equiv). The mixture was stirred at 110° C. for 14 h,and then cooled to 45° C. prior to the addition of a solution of LiOH(28 mg, 1.2 mmol, 3 equiv) in 2:1 THF/H₂O (1 mL). After 3 h at 45° C.,the reaction mixture was purified by preparative reversed-phase HPLC(acetonitrile/water) to afford the title compound (50 mg, 50%). HPLC:R_(t)=3.62 (Method A). MS (ESI): mass calculated for C₂₈H₂₇N₃O₃, 453.21;m/z found, 454.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.43-7.39 (m, 3H),7.25-7.17 (m, 3H), 7.10-7.06 (m, 6H), 6.24 (s, 1H), 4.09 (dd, J=10.0,5.2 Hz, 1H), 3.53 (dd, J=15.0, 10.0 Hz, 1H), 3.13-3.09 (dd, J=15.0, 5.2Hz, 1H), 2.34 (s, 6H), 2.16 (S, 3H).

The compounds of Examples 103 and 104 were made according to thesynthetic methods outlined in Example 102 and Scheme L.

Example 103

3-{5-[4-(Formyl-methyl-amino)-phenyl]-1-p-tolyl-1H-pyrazol-3-yl}-2-m-tolyl-propionicacid

HPLC: R_(t)=3.64 (Method A). MS (ESI): mass calculated for C₂₈H₂₇N₃O₃,453.21; m/z found, 454.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.50 (s, 1H),7.25-7.08 (m, 8H), 7.19 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.5 Hz, 2H), 6.24(s, 1H), 4.11 (dd, J=9.6, 5.7 Hz, 1H), 3.55 (dd, J=15.0, 9.6 Hz, 1H),3.30 (s, 3H), 3.14 (dd, J=15.0, 5.7 Hz, 1H), 2.36 (s, 3H), 2.24 (s, 3H).

Example 104

3-{5-[4-(2-Oxo-pyrrolidin-1-yl)-phenyl]-1-p-tolyl-1H-pyrazol-3-yl}-2-m-tolyl-propionicacid

HPLC: R_(t)=3.75 (Method A). MS (ESI): mass calculated for C₃₀H₂₉N₃O₃,479.22; m/z found, 480.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.54 (d, J=8.8Hz, 2H), 7.24-7.09 (m, 8H), 7.14 (d, J=8.8 Hz, 2H), 6.20 (s, 1H),4.10(dd, J=9.3, 5.7 Hz, 1H), 3.83 (t, J=7.0 Hz, 2H), 3.54 (dd, J=15.0,9.3 Hz, 1H), 3.13 (dd, J=15.0, 5.7 Hz, 1H), 2.62 (t, J=8.2 Hz, 2H), 2.37(s, 3H), 2.24 (s, 3H), 2.16 (quintet, J=8.0, 7.0 Hz, 2H).

Example 105

3-[5-Naphthalen-2-yl-1-(1-oxy-pyridin-2-yl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

To a solution of3-(5-naphthalen-2-yl-1-pyridin-2-yl-1H-pyrazol-3-yl)-2-m-tolyl-propionicacid (Example 52; 10 mg, 0.02 mmol) in THF (0.6 mL) was addedm-chloroperbenzoic acid (7 mg, 0.03 mmol, 1.5 equiv). The reactionmixture was stirred at room temperature for 3 h, and then diluted withCH₂Cl₂ (2 mL). A solution of 1 N NaOH (1 mL) was added, and theresulting aqueous layer was back-extracted with CH₂Cl₂ (2×2 mL). Thecombined organic layers were washed with brine (2 mL), dried (MgSO₄),and concentrated under reduced pressure. The residue was purified bypreparative reversed-phase HPLC (acetonitrile/water) to afford the titlecompound (6 mg, 60%). HPLC: R_(t)=1.17 (Method H). MS (ESI): masscalculated for C₂₈H₂₃N₃O₃, 449.17; m/z found, 450.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 8.25 (s, 1H), 7.78-7.69 (m, 5H), 7.48-7.39 (m, 4H),7.35-7.30 (m, 1H), 7.30-7.20 (m, 3H), 7.10 (d, J=6.3 Hz, 1H), 4.14 (dd,J=10.0, 5.7 Hz, 1H), 3.59 (dd, J=15.0, 10.0, 1H), 3.12 (dd, J=15.0, 5.7Hz, 1H), 2.34 (s, 3H).

Example 106

3-(5-Quinolin-6-yl-1-p-tolyl-1H-pyrazol-3-yl)-2-m-tolyl-propionic acid

To a solution of3-[5-(4-allylamino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid ethyl ester (Example 94, Step A; 70 mg, 0.15 mmol) in ethanol (1mL) was added 10% Pd/C (26 mg) and methanesulfonic acid (0.01 mL, 0.15mmol, 1 equiv). The mixture was stirred at 65° C. for 2 h. The catalystwas removed by filtering the reaction mixture through a CELITE® pad, andthe pad was rinsed with EtOH (1.5 mL). The combined filtrates wereconcentrated under reduced pressure. The crude residue was dissolved in1:1 THF/H₂O (1.5 mL), and LiOH was added (10 mg, 0.45 mmol, 3 equiv).After 3 h at 45° C., the mixture was purified by preparativereversed-phase HPLC (acetonitrile/water) to afford the title compound(26 mg, 35%) along with3-[5-(4-amino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid (20 mg, 35%). HPLC: R_(t)=3.18 (Method A). MS (ESI): masscalculated for C₂₉H₂₅N₃O₂, 447.19; m/z found, 448.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 8.43 (d, J=8.5 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H), 7.85 (d,J=1.7 Hz, 1H), 7.68 (dd, J=8.3, 4.8 Hz, 1H), 7.59 (dd, J=8.8, 1.7 Hz,1H), 7.26-7.23 (m, 2H), 7.12 (s, 4H), 6.42 (s, 1H), 4.17 (dd, J=9.8, 5.3Hz, 1H), 3.58 (dd, J=14.9, 9.8 Hz, 1H), 3.17 (dd, J=14.9, 5.3 Hz, 1H),2.36 (s, 3H).

Example 107

3-[5-(4-Amino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

Prepared according to the synthetic methods outlined in Example 106.HPLC: R_(t)=3.16 (Method A). MS (ESI): mass calculated for C₂₆H₂₅N₃O₂,411.19; m/z found, 412.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.30 (s, 2H),7.24-7.21 (m, 2H), 7.13-7.07 (m, 4H), 6.97 (d, J=8.3 Hz, 2H), 6.67 (d,J=6.8 Hz, 2H), 6.13 (s, 1H), 4.01 (dd, J=9.3, 6.0 Hz, 1H), 3.49 (dd,J=14.6, 9.3 Hz, 1H), 3.07 (dd, J=14.6, 6.0 Hz, 1H), 2.34 (s, 6H).

Example 108

(Preparation of Alkenes)

(Z)-2-(3-Chloro-phenyl)-3-[5-(3,4-dichloro-phenyl)-1-(4-ethoxy-phenyl)-1H-pyrazol-3-yl]-acrylicacid

A.5-(3,4-Dichloro-phenyl)-1-(4-ethoxy-phenyl)-1H-pyrazole-3-carbaldehyde.To a solution of Dess-Martin periodinane (2.0 g, 4.6 mmol, 2.0 equiv) inCH₂Cl₂ (10 mL) was added a solution of[5-(3,4-dichloro-phenyl)-1-(4-ethoxy-phenyl)-1H-pyrazol-3-yl]-methanol(prepared by the method of Example 1, Steps A-C; 0.84 g, 2.3 mmol) inCH₂Cl₂ (10 mL). The reaction mixture was stirred overnight at roomtemperature. Then the reaction was quenched with 1 M NaOH (10 mL), andthe resulting mixture was stirred until the layers separated. Theaqueous layer was back-extracted with CH₂Cl₂ (3×10 mL). The combinedorganic layers were washed with 1 M NaOH (20 mL) then H₂O (20 mL), dried(MgSO₄), and concentrated to provide the pure aldehyde as a dark brownoil (0.59 g, 1.6 mmol, 70%). TLC (silica gel, 1:1 EtOAc/hexanes):R_(f)=0.62. MS (ESI): mass calculated for C₁₈H₁₄Cl₂N₂O₂, 360.04; m/zfound, 361 [M+H]⁺. ¹H NMR (400 mHz, CDCl₃): 10.05 (s, 1H), 7.38-7.36 (m,2H), 7.25-7.21 (m, 2H), 7.0 (s, 1H), 7.0-6.97 (m, 1H), 6.93-6.91 (m,2H), 4.06 (q, J=7.0 Hz), 1.44 (t, J=7.0 Hz, 3H).

B.2-(3-Chloro-phenyl)-3-[5-(3,4-dichloro-phenyl)-1-(4-ethoxy-phenyl)-1H-pyrazol-3-yl]-acrylicacid. E and Z stereoisomers. To a mixture of5-(3,4-dichloro-phenyl)-1-(4-ethoxy-phenyl)-1H-pyrazole-3-carbaldehyde(0.33 g, 0.91 mmol) and 3-chlorophenyl acetic acid (0.23 g, 1.4 mmol)was added acetic anhydride (0.8 mL) and TEA (0.8 mL). The mixture wasallowed to stir overnight at room temperature. The TEA was removed underreduced pressure, and the resulting mixture was purified on silica gel(MPLC, 0-5% MeOH/CH₂Cl₂) to provide exclusively the E acrylic acid as abrown foam (0.21 g, 46%). The foam was then dissolved in CHCl₃ (10 mL),and the solution was placed in quartz tubes and subjected to uv lightovernight. The solvent was removed to provide a 1:1 mixture of E and Zstereoisomers. The stereoisomers were separated by preparativereversed-phase HPLC (acetonitrile/water) to afford the pure Z (0.033 g,0.064 mmol, 15%) and E acrylic acids (0.043 g, 0.084 mmol, 20%). Zstereoisomer: TLC (silica gel, 9:1 CH₂Cl₂/MeOH): R_(f)=0.26. HPLC:R_(t)=7.35 (Method I). MS (ESI): mass calculated for C₂₆H₁₉Cl₃N₂O₃,512.05; m/z found, 511/513 [M−H]⁻. ¹H NMR (400 mHz, CDCl₃): 7.49-7.47(m, 1H), 7.39-7.31 (m, 5H), 7.19-7.16 (m, 2H), 7.05(s, 1H), 6.99-6.96(m, 1H), 6.90-6.86 (m, 2H), 4.04 (q, J=7.0 Hz) 6.72 (s, 1H), ): 1.44 (t,J=7.0 Hz, 3H).

Example 109

(E)-2-(3-Chloro-phenyl)-3-[5-(3,4-dichloro-phenyl)-1-(4-ethoxy-phenyl)-1H-pyrazol-3-yl]-acrylicacid

HPLC: R_(t)=8.58. MS (ESI): mass calculated for C₂₆H₂₅N₃O₂, 512.0; m/zfound, 513 [M+H]⁺. ¹H NMR (400 mHz, CDCl₃): 8.09 (s, 1H), 7.30 (m, 3H),7.24 (m, 2H), 7.14 (m, 3H), 6.86 (m, 2H), 6.79 (m, 1H), 5.53 (s, 1H),4.03 (q, J=7.0 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H).

Example 110

(Z)-2-(3-Chloro-phenyl)-3-[5-(3,4-dichloro-phenyl)-1-pyridin-2-yl-1H-pyrazol-3-yl]-acrylicacid

This compound was prepared as described for the 4-ethoxyphenyl analog inEXAMPLE 108 substituting[5-(3,4-dichloro-phenyl)-1-pyridin-2-yl-1H-pyrazol-3-yl]-methanol(prepared by the method of Example 1, Steps A-C)for{5-(3,4-dichloro-phenyl)-1-(4-ethoxy-phenyl)-1H-pyrazol-3-yl]-methanolin Step A. TLC (silica gel, 9:1 CH₂Cl₂/MeOH): R_(f)=0.19. HPLC:R_(t)=5.63 (Method I). MS (ESI): mass calculated for C₂₃H₁₄Cl₃N₃O₂,469.02; m/z found, 468/469 (M−H]⁻. ¹H NMR (400 mHz, CDCl₃): 8.26-8.25(m, 1H), 7.79-7.77 (m, 1H), 7.58-7.56 (m, 1H), 7.47-7.46 (m, 1H),7.37-7.22 (m, 6H), 7.02 (s, 1H), 7.00-6.98 (m, 1H), 6.74 (s, 1H).

Example 111

(Z)-2-(3-Chloro-phenyl)-3-[5-(3,4-dichloro-phenyl)-1-(2,5-dichloro-phenyl)-1H-pyrazol-3-yl]-acrylicacid

This compound was prepared as described for the 4-ethoxyphenyl analog inEXAMPLE 108 substituting[5-(3,4-dichloro-phenyl)-1-(2,5-dichloro-phenyl)-1H-pyrazol-3-yl]-methanolfor[5-(3,4-dichloro-phenyl)-1-(4-ethoxy-phenyl)-1H-pyrazol-3-yl]-methanolin Step A. TLC (silica gel, 9:1 CH₂Cl₂/MeOH): R_(f)=0.23. HPLC:R_(t)=7.95 (Method I). MS (ESI): mass calculated for C₂₄H₁₃Cl₅N₂O₂,535.94; m/z found, 535/537 [M−H]⁻. ¹H NMR (400 mHz, CDCl₃): 7.51-7.49(m, 2H), 7.45-7.32 (m, 7H), 7.07 (s, 1H), 6.97-6.94 (m, 1H), 6.82 (s,1H).

Example 112

(Z)-2-(3-Chloro-phenyl)-3-[1-(2,5-dichloro-phenyl)-5-naphthalen-2-yl-1H-pyrazol-3-yl]-acrylicacid

HPLC: R_(t)=5.28 (Method I). MS (ESI): mass calculated forC₂₈H₁₇Cl₃N₂O₂, 518.04; m/z found, 519/521 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 7.83-7.72 (m, 4H), 7.54-7.51 (m, 4H), 7.42-7.38 (m, 4H),7.35-7.33 (m, 2H), 7.11 (s, 1H), 6.87 (s, 1H).

Example 113

(Z)-2-(3-Chloro-phenyl)-3-[1-(4-ethoxy-phenyl)-5-naphthalen-2-yl-1H-pyrazol-3-yl]-acrylicacid

HPLC: R_(t)=5.23 (Method I). MS (ESI): mass calculated for C₃₀H₂₃ClN₂O₃,494.14; m/z found, 495.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.84-7.83 (m,2H), 7.80-7.77 (m, 2H), 7.56-7.52 (m, 2H), 7.49-7.48 (m, 1H), 7.39-7.37(m, 1H), 7.33-7.32 (m, 2H), 7.26-7.24 (m, 3H), 7.08 (s, 1H), 6.86 (d,J=9.0 Hz, 2H), 6.77 (s, 1H), 4.03 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.1 Hz,1H).

Example 114

(Z)-3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-phenyl-acrylicacid

HPLC: R_(t)=10.60 (Method A). MS (ESI): mass calculated forC₂₅H₁₈Cl₂N₂O₃, 464.07; m/z found, 465.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.50-7.48 (m, 2H), 7.39-7.35 (m, 5H), 7.23 (d, J=9.0 Hz, 2H), 7.06 (s,1H), 6.99 (dd, J=8.2, 1.9 Hz, 1H), 6.91 (d, J=9.0 Hz, 2H), 6.70 (s, 1H),3.85 (s, 3H).

Example 115

(Z)-2-(3-Chloro-phenyl)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-acrylicacid

HPLC: R_(t)=10.50 (Method A). MS (ESI): mass calculated forC₂₅H₁₇Cl₃N₂O₃, 498.03; m/z found, 499.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.47 (br s, 1H), 7.41 (s, 2H), 7.39-7.37 (m, 1H), 7.35 (s, 2H), 7.22 (d,J=9.0 Hz, 2H), 7.04 (s, 1H), 7.00 (dd, J=8.2, 2.2 Hz, 1H), 6.92 (d,J=9.0 Hz, 2H), 6.70 (s, 1H), 3.85 (s, 3H).

Example 116

(Z)-2-(4-Chloro-phenyl)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-acrylicacid

HPLC: R_(t)=10.50 (Method A). MS (ESI): mass calculated forC₂₅H₁₇Cl₃N₂O₃, 498.03; m/z found, 499.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.43-7.40 (m, 4H), 7.36(d, J=8.8 Hz, 2H), 7.22 (d, J=9.0 Hz, 2H), 7.02(s, 1H), 6.99 (dd, J=8.2, 2.2 Hz, 1H), 6.92 (d, J=9.0 Hz, 2H), 6.70 (s,1H), 3.85 (s, 3H).

Example 117

(Z)-3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-(4-methoxy-phenyl)-acrylicacid

HPLC: R_(t)=5.60 (Method A). MS (ESI): mass calculated forC₂₆H₂₀Cl₂N₂O₄, 494.08; m/z found, 495.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.44 (d, J=8.8 Hz, 2H), 7.40 (d, J=2.2 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H),7.21 (d, J=9.0 Hz, 2H), 7.00 (s, 1H), 6.96 (dd, J=8.5, 1.9 Hz, 1H), 6.9?(d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.68 (s, 1H), 3.85 (s, 3H),3.84 (s, 3H).

Example 118

(Z)-2-(3,4-Dichloro-phenyl)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-acrylicacid

HPLC: R_(t)=6.20 (Method A). MS (ESI): mass calculated forC₂₅H₁₆Cl₄N₂O₃, 531.99; m/z found, 533.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.58 (d, J=1.9 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.41-7.39 (m, 2H), 7.32(dd, J=8.5, 2.2 Hz, 1H), 7.22 (d, J=9.0 Hz, 2H), 7.03 (s, 1H), 6.99 (dd,J=8.2, 1.9 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 6.71 (s, 1H), 3.86 (s, 3H).

Example 119

(Z)-3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-p-tolyl-acrylicacid

HPLC: R_(t)=6.94 (Method A). MS (ESI): mass calculated forC₂₆H₂₀Cl₂N₂O₃, 478.09; m/z found, 479.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.40-7.38 (m, 4H), 7.22-7.19 (m, 4H), 7.03 (s, 1H), 6.99 (dd, J=8.2, 1.9Hz, 1H), 6.91 (d, J=9.0 Hz, 2H), 6.69 (s, 1H), 3.85 (s, 3H), 2.38 (s,3H).

Example 120

(Z)-3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-acrylicacid

HPLC: R_(t)=6.79 (Method A). MS (ESI): mass calculated forC₂₆H₂₀Cl₂N₂O₃, 478.09; m/z found, 479.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.40 (d, J=2.2 Hz, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.30-7.28 (m, 3H), 7.21(d, J=9.0 Hz, 2H), 7.18-7.15 (m, 1H), 7.04 (s, 1H), 6.99 (dd, J=8.2, 1.9Hz, 1H), 6.91 (d, J=9.0 Hz, 2H), 6.70 (s, 1H), 3.85 (s, 3H), 2.39 (s,3H).

Example 121

(Z)-3-[5-Benzo[1,3]dioxol-5-yl-1-(4-ethoxy-phenyl)-1H-pyrazol-3-yl]-2-(3-chloro-phenyl)-acrylicacid

HPLC: R_(t)=6.38 (Method I). MS (ESI): mass calculated for C₂₇H₂₁ClN₂O₅,488.11; m/z found, 489.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.48 (br s,1H), 7.36-7.35 (m, 1H), 7.31-7.30 (m, 2H), 7.23 (d, J=9.0 Hz, 2H), 7.02(s, 1H), 6.89 (d, J=9.0 Hz, 2H), 6.79 (d, J=7.9 Hz, 1H), 6.75 (dd,J=8.2, 1.6 Hz, 1H), 6.67 (d, 1.6 Hz, 1H), 6.58 (s, 1H), 6.00 (s, 2H),4.06 (q, J=6.9 Hz, 2H), 1.44 (t, 6.9 Hz, 3H).

Example 122

(Z)-3-[5-Benzo[1,3]dioxol-5-yl-1-(2,5-dichloro-phenyl)-1H-pyrazol-3-yl]-2-(3-chloro-phenyl)-acrylicacid

A.5-Benzo[1,3]dioxol-5-yl-1-(2,5-dichloro-phenyl)-1H-pyrazole-3-carbaldehyde.To a solution of Dess-Martin periodinane (2.3 g, 5.5 mmol, 2.0 equiv) inCH₂Cl₂ (10 mL) was added a solution of[5-benzo[1,3]dioxol-5-yl-1-(2,5-dichloro-phenyl)-1H-pyrazol-3-yl]-methanol(prepared by the method of Example 1, Steps A-C; 1.0 g, 2.8 mmol) inCH₂Cl₂ (10 mL). The reaction mixture was stirred overnight at roomtemperature. Then the reaction was quenched with 1 M NaOH (10 mL), andthe resulting mixture was stirred until the layers separated. Theaqueous layer was back-extracted with CH₂Cl₂ (3×10 mL). The combinedorganic layers were washed with 1 M NaOH (20 mL) then H₂O (20 mL), dried(MgSO₄), and concentrated to provide the pure aldehyde (1.04 g, 2.8mmol, 99%). HPLC: R_(t)=5.35 (Method B). MS (ESI): mass calculated forC₁₇H₁₀Cl₂N₂O₃, 360.01; m/z found, 361 [M+H]⁺. ¹H NMR (400 mHz, CDCl₃):10.05 (s, 1H), 7.50-7.43 (m, 1H), 7.25-7.21 (m, 2H), 7.7-7.26 (m, 1H),6.96 (s, 1H), 6.74-6.72 (m, 1H), 6.68-6.65 (m, 2H), 5.97 (s, 2H).

B.3-[5-Benzo[1,3]dioxol-5-yl-1-(2,5-dichloro-phenyl)-1H-pyrazol-3-yl]-2-(3-chloro-phenyl)-acrylicacid. E and Z stereoisomers. To a mixture of5-benzo[1,3]dioxol-5-yl-1-(2,5-dichloro-phenyl)-1H-pyrazole-3-carbaldehyde(0.20 g, 0.55 mmol) and 3-chlorophenyl acetic acid (0.19 g, 0.82 mmol)was added acetic anhydride (1.0 mL) and TEA (1.0 mL). The mixture wasallowed to stir overnight at room temperature. The TEA was removed underreduced pressure, and the resulting mixture was purified on silica gel(MPLC, 0-5% MeOH/CH₂Cl₂) to provide exclusively the E acrylic acid as abrown foam (0.14 g, 49%). The foam was then dissolved in CHCl₃ (10 mL),and the solution was placed in quartz tubes and subjected to uv/vislight overnight. The solvent was removed to provide a 1:1 mixture of Eand Z stereoisomers. The stereoisomers were separated by preparativereversed-phase HPLC (acetonitrile/water) to afford the pure Z (0.02 g,0.04 mmol, 15%) and E acrylic acids (0.03 g, 0.04 mmol, 20%). Zstereoisomer: HPLC: R_(t)=5.86 (Method I). MS (ESI): mass calculated forC₂₅H₁₅Cl₃N₂O₄, 512.01; m/z found, 513.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.48 (br s, 1H), 7.45 (br s, 1H), 7.43 (s, 2H), 7.38-7.36 (m, 1H),7.32-7.31 (m, 2H), 7.06 (s, 1H), 6.75 (d, J=8.5 Hz, 1H), 6.69 (s, 1H),6.68 (d, J=8.2 Hz, 2H), 5.99 (s, 2H).

Example 123

(E)-3-[5-Benzo[1,3]dioxol-5-yl-1-(2,5-dichloro-phenyl)-1H-pyrazol-3-yl]-2-(3-chloro-phenyl)-acrylicacid

HPLC: R_(t)=4.82 (Method I). MS (ESI): mass calculated forC₂₅H₁₅Cl₃N₃O₂, 512.0; m/z found, 513 [M+H]⁺. ¹H NMR (500 mHz, CDCl₃):8.05 (s, 1H), 7.43-7.34 (m, 3H), 7.26-7.24 (m, 4H), 6.65 (d, J=8.5 Hz,1H), 6.45-6.43 (m, 2H), 5.93 (s, 2H), 5.49 (s, 1H).

Example 124

(E)-2-(3.4-Dichloro-phenyl)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-acrylicacid

HPLC: R_(t)=6.22 (Method I). MS (ESI): mass calculated forC25H₁₆Cl₄N₂O₃, 531.99; m/z found, 532.9 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):8.09 (s, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.47 (d, J=1.9 Hz, 1H), 7.33 (d,J=8.2 Hz, 1H), 7.21 (dd, J=8.2, 1.9 Hz, 1H), 7.15 (s, 1H), 7.14 (d,J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.83 (dd, J=8.5, 2.2 Hz, 1H),5.68 (s, 1H), 3.83 (s, 3H).

Example 125

(E)-3-[5-Benzo[1,3]dioxol-5-yl-1-(4-ethoxy-phenyl)-1H-pyrazol-3-yl]-2-(3-chloro-phenyl)-acrylicacid

HPLC: R_(t)=6.28 (Method I). MS (ESI): mass calculated for C₂₇H₂₁ClN₂O₅,488.11; m/z found, 489.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.09 (s, 1H),7.40-7.38 (m, 3H), 7.26-7.23 (m, 1H), 7.16 (d, J=9.0 Hz, 2H), 6.85 (d,J=8.8 Hz, 2H), 6.68 (d, J=7.9 Hz, 1H), 6.50 (dd, J=7.9, 1.6 Hz, 1H),6.45 (d, J=1.6 Hz, 1H), 5.93 (s, 2H), 5.46 (s, 1H), 4.03 (q, J=6.9 Hz,2H), 1.42 (t, J=6.9 Hz, 3H).

Example 126

(Reduction)

2-(3-Chloro-phenyl)-3-[5-(3,4-dichloro-phenyl)-1-(4-ethoxy-phenyl)-1H-pyrazol-3-yl]-propionicacid

To a solution of2-(3-chloro-phenyl)-3-[5-(3,4-dichloro-phenyl)-1-(4-ethoxy-phenyl)-1H-pyrazol-3-yl]-acrylicacid (Example 108, Step B; 0.043 g, 0.084 mmol) in EtOH (5 mL) was addedtosylhydrazine (0.22 g, 1.2 mmol). To the light yellow solution wasadded a mixture of NaOAc (0.098 g, 1.2 mmol) in H₂O (1 mL). Theresulting mixture was heated to 100° C. overnight, then cooled to rt,diluted with H₂O (10 mL), and extracted with CH₂Cl₂ (3×10 mL). Thecombined organic layers were dried (MgSO₄) and then concentrated toprovide a yellow oil. The oil was purified by preparative reversed-phaseHPLC (acetonitrile/water) to afford the pure alkane as a colorless oil(10 mg, 23%). TLC (silica gel, 9:1 CH₂Cl₂/MeOH): R_(f)=0.43. HPLC:R_(t)=10.7 (Method A). MS (ESI): mass calculated for C₂₆H₂₁Cl₃N₂O₃,514.06; m/z found, 513 [M−H]⁻. ¹H NMR (400 mHz, CDCl₃): 7.32-7.23 (m,6H), 7.14-7.10 (m, 2H), 6.92-6.89 (m, 1H), 6.88-6.85 (m, 2H), 6.23 (s,1H), 4.03 (q, J=6.9 Hz, 2H), 4.04-4.00 (m, 1H), 3.50 (dd, J=6.7, 14.7Hz, 1H), 3.09 (dd, J=8.7, 14.7 Hz, 1H), (1.42 (t, J=7.0 Hz, 3H),

The compounds of Examples 127 and 128 were made according to thesynthetic methods outlined in Example 126 and Scheme H.

Example 127

2-(3-Chloro-phenyl)-3-[1-(2,5-dichloro-phenyl)-5-naphthalen-2-yl-1H-pyrazol-3-yl]-propionicacid

HPLC: R_(t)=4.77 (Method B). MS (ESI): mass calculated forC₂₈H₁₉Cl₃N₂O₂, 520.05; m/z found, 521/523 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.79-7.77 (m, 1H), 7.73-7.68 (m, 2H), 7.61-7.60 (m, 1H),7.48-7.46 (m, 3H), 7.38-7.37 (m, 1H), 7.31-7.26 (m, 4H), 7.20 (dd,J=8.5, 1.8 Hz, 1H), 6.35 (s, 1H), 4.16 (dd, J=8.3, 7.0 Hz, 1H), 3.54(dd, J=14.8, 8.3 Hz, 1H), 3.19(dd, J=14.8, 7.0 Hz, 1H).

Example 128

2-(3-Chloro-phenyl)-3-[1-(4-ethoxy-phenyl)-5-naphthalen-2-yl-1H-pyrazol-3-yl]-propionicacid

HPLC: R_(t)=5.07 (Method A). MS (ESI): mass calculated for C₃₀H₂₅ClN₂O₃,497.0; m/z 497.1 [M+H]⁺. ¹H NMR (500 mHz, CDCl₃): 7.80-7.78 (m, 1H),7.74-7.70 (m, 3H), 7.50-7.48 (m, 2H), 7.39 (s, 1H), 7.28-7.26 (m, 3H),7.18-7.14 (m, 3H), 6.80 (d, J=8.8 Hz, 2H), 6.36 (s, 1H), 4.16 (dd,J=9.3, 6.0 Hz, 1H), 4.00 (q, J=6.8 Hz, 2H), 3.58 (dd, J=15.0, 9.3 Hz,1H), 3.19 (dd, J=15.0, 6.0 Hz, 1H), 1.40 (t, J=6.8 Hz, 3H).

The compounds of Examples 129-132 were made according to the syntheticmethods outlined in Scheme D.

Example 129

(Preparation of Tetrazoles)

5-{(S)-2-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-1-m-tolyl-ethyl}-1H-tetrazole

A.(S)-N-2-Cyano-ethyl)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionamide.To a 3-neck round-bottom flask was added(S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid (Example 1; 5.0 g, 9.9 mmol, 1.0 equiv), EDC (4.7 g, 24.7 mmol, 2.5equiv) and HOBT (3.3 g, 24.7 mmol, 2.5 equiv) under nitrogen.N,N-Dimethylformamide (50 mL) was added, followed by3-aminopropanenitrile (1.9 g, 24.7 mmol, 2.5 equiv) anddiisopropylethylamine (6.8 mL, 39.6 mmol, 4.0 equiv). The reactionmixture was stirred overnight, then was diluted with ethyl acetate (200mL), washed with 1 N HCl (100 mL), H₂O (100 mL), 10% sodium bicarbonate(100 mL), H₂O (100 mL) then brine (100 mL), and dried (sodium sulfate).The solvent was then removed under reduced pressure yielding the desiredamide (5.35 g, 99%), which was used in the next step withoutpurification. HPLC: R_(t)=7.89 (Method A). MS (ESI): mass calculated forC₂₉H₂₆Cl₂N₄O₂, 532.14; m/z found, 533.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.31-7.30 (m, 2H), 7.23 (t, J=7.4 Hz, 1H), 7.19 (br s, 1H), 7.16-7.14(m, 3H), 7.10 (d, J=7.4 Hz, 1H), 6.91 (dd, J=8.5, 2.2 Hz, 1H), 6.87 (d,J=9.0 Hz, 2H), 6.20 (s, 1H), 6.09 (t, J=6.0 Hz, 1H), 3.90 (dd, J=9.0,6.0 Hz, 1H), 3.82 (s, 3H), 3.56-3.50 (m, 2H), 3.35-3.31 (m, 1H), 3.08(dd, J=14.8, 6.0 Hz, 1H), 2.53-2.46 (m, 2H), 2.35 (s, 3H).

B.3-(5-{(S)-2-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-1-m-tolyl-ethyl}-tetrazol-1-yl)-propionitrile.A 3-neck round-bottom flask was charged with(S)-N-(2-cyano-ethyl)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionamide(4.0 g, 7.5 mmol, 1.0 equiv) and triphenyl phosphine (4.91 g, 18.8 mmol,2.5 equiv) under nitrogen. Acetonitrile was added, and the mixture wasstirred at room temperature until all of the solids dissolved. Thesolution was then cooled to 0° C., and diisopropyl azodicarboxylate(3.79 mL, 18.8 mmol, 2.5 equiv) was added slowly via syringe. After theresulting mixture had stirred for 5 min, trimethylsilyl azide (3.0 mL,22.5 mmol, 3 equiv) was added via syringe over 20 min. The reactionmixture was allowed to warm to room temperature and was stirred for 30min, and then was stirred at 50° C. for 14 h. The mixture was cooled toroom temperature, then to 0° C., and a solution of sodium nitrite (685mg) in water (3.3 mL) was added. After 20 min a solution of cerricammonium nitrate (5.5 g) in water (15.5 mL) was added, and the resultingmixture was stirred for 30 min. The mixture was then added to water (200mL), and the resulting solution was extracted with dichloromethane(2×100 mL). The combined extracts were washed with brine (100 mL), dried(Na₂SO₄), and concentrated under reduced pressure. The crude residue waspurified by flash chromatography (25% ethyl acetate/dichloromethane)yielding the desired protected tetrazole (2.1 g, 50%). HPLC: R_(t)=8.18(Method A). MS (ESI): mass calculated for C₂₉H₂₅Cl₂N₇O, 557.15; m/zfound, 558.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.30 (d, J=8.2 Hz, 1H),7.28-7.25 (m, 3H), 7.17-7.15 (m, 3H), 7.06 (d, J=9.0 Hz, 2H), 6.89-6.86(m, 3H), 6.24 (s, 1H), 4.75 (dd, J=10.2, 5.3 Hz, 1H), 4.45-4.43 (m, 2H),3.92 (dd, J=15.2, 10.2 Hz, 1H), 3.83 (s, 3H), 3.42 (dd, J=15.2, 5.3 Hz,1H), 2.85-2.75 (m, 1H), 2.53-2.49 (m, 1H), 2.34 (s, 3H).

C.5-{(S)-2-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-1-m-tolyl-ethyl}-1H-tetrazole.To a solution of3-(5-{(S)-2-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-1-m-tolyl-ethyl}-tetrazol-1-yl)-propionitrile(1.5 g, 2.7 mmol) in dichloromethane (25 mL) was added DBU (2.9 mL, 18.9mmol, 7.0 equiv), and the mixture was stirred at room temperature for 48h. Dichloromethane (200 mL) was added, and the resulting mixture waswashed with 1 N HCl (2×100 mL) then water (100 mL), dried (Na₂SO₄), andconcentrated under reduced pressure. The crude residue was purified byflash chromatography (50% dichloromethane/ethyl acetate) to afford thetitle compound (1.3 grams, 95%). HPLC: R_(t)=5.31 (Method A). MS (ESI):mass calculated for C₂₆H₂₂Cl₂N₆O, 504.12; m/z found, 505.3 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 7.32 (d, J=8.2 Hz, 1H), 7.28-7.24 (m, 3H), 7.21(t, J=7.7 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 7.08 (d, J=7.7 Hz, 1H),6.95-6.94 (m, 3H), 6.88 (dd, J=8.5, 2.2 Hz, 1H), 6.18 (s, 1H), 4.85 (dd,J=9.0, 3.6 Hz, 1H), 3.86 (s, 3H), 3.58 (dd, J=14.8, 8.5 Hz, 1H), 3.42(dd, J=15.4, 3.6 Hz, 1H), 2.31 (s, 3H).

Example 130

(Preparation of Tetrazoles)

5-{2-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-1-m-tolyl-ethyl)-1H-tetrazole

A.3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionitrile.To a solution of sodium bis(trimethylsilyl)amide (14.0 mL, 1.0 Msolution in THF, 1.0 equiv) in tetrahydrofuran (56.0 mL) at 0° C. wasadded 3-methylbenzyl cyanide (1.84 g, 14.0 mmol, 1.0 equiv). Thismixture was stirred at 0° C. for 30 min then was added to a solution of3-bromomethyl-5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole(prepared as in Method 1; 5.78 g, 14.0 mmol, 1.0 equiv) intetrahydrofuran (56.0 mL) and allowed to stir for 2 h. The reaction wasquenched with satd aq ammonium chloride (10.0 mL), and the resultingmixture was diluted with water (200 mL), and extracted with diethylether (2×100 mL). The combined extracts were dried (Na₂SO₄) andconcentrated under reduced pressure. The crude material was purified byflash chromatography (25% ethyl acetate/hexanes) to yield the titleintermediate (2.76 g, 43%). HPLC: R_(t)=13.44 (Method G). MS (ESI): masscalculated for C₂₆H₂₁Cl₂N₃O, 461.11; m/z found, 462.0 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 7.36 (d, J=1.9 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.28(t, J=7.4 Hz, 1H), 7.24 (s, 1H), 7.23-7.21 (m, 1H), 7.18 (d, J=8.8 Hz,2H), 7.19-7.16 (m, 1H), 6.95 (dd, J=8.5, 2.2 Hz, 1H), 6.89 (d, J=8.8 Hz,2H), 6.42 (s, 1H), 4.22 (dd, J=9.6, 6.0 Hz, 1H), 3.83 (s, 3H), 3.30-3.21(m, 2H), 2.38 (s, 3H).

B.5-{2-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-1-m-tolyl-ethyl}-1H-tetrazole.To a 48-mL pressure vessel (Chemglass) were added N,N-dimethylformamide(25.0 mL),3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionitrile(2.76 g, 5.97 mmol, 1.0 equiv), ammonium chloride (1.58 g, 29.8 mmol,5.0 equiv) and sodium azide (1.94 g, 29.8 mmol, 5.0 equiv). Thescrew-cap vessel was sealed and then placed in an oil bath heated to 90°C. for 48 h. The reaction mixture was cooled to room temperature,pH-adjusted with formic acid, diluted with water (100 mL), and extractedwith ethyl acetate (3×50 mL). The combined extracts were washed withwater (3×50 mL) then brine (50 mL), dried (Na₂SO₄), and concentratedunder reduced pressure. The crude material was purified by flashchromatography (5% methanol/dichloromethane) to yield the title compound(1.9 g, 63%). HPLC: R_(t)=3.09 (Method A). MS (ESI): mass calculated forC₂₆H₂₂Cl₂N₆O, 504.12; m/z found, 505.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): 7.57 (d, J=8.5 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.23-7.16 (m,3H), 7.09-7.07 (m, 3H), 7.01 (dd, J=8.5, 2.2 Hz, 1H), 6.96 (d, J=9.0 Hz,2H), 6.46 (s, 1H), 4.86 (dd, J=9.0, 6.6 Hz, 1H), 3.77 (s, 3H), 3.62 (dd,J=14.8, 9.3 Hz, 1H), 3.35 (dd, J=14.8, 6.6 Hz, 1H), 2.28 (s, 3H).

Example 131

5-{(R)-2-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-1-m-tolyl-ethyl}-1H-tetrazole

This compound was obtained by chiral-HPLC separation of the twoenantiomers (Method C) from the racemic mixture prepared in Example 130.HPLC: R_(t)=5.31 (Method A). MS (ESI): mass calculated for C₂₆H₂₂Cl₂N₆O,504.12; m/z found, 505.3 {M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.32 (d, J=8.2Hz, 1H), 7.28-7.26 (m, 3H), 7.21 (t, J=7.7 Hz, 1H), 7.15 (d, J=8.8 Hz,2H), 7.08 (d, J=7.7 Hz, 1H), 6.94 (m, 3H),6.88 (dd, J=8.5, 2.2 Hz, 1H),6.18 (s, 1H), 4.85 (dd, J=9.0, 3.6 Hz, 1H), 3.86 (s, 3H), 3.58 (dd,J=14.8, 8.5 Hz, 1H), 3.42 (dd, J=15.4, 3.6 Hz, 1H), 2.31 (s, 3H).

Example 132

5-[2-[5-Benzo[1,3]dioxol-5-yl-1-(2,5-dichloro-phenyl)-1H-pyrazol-3-yl]-1-(3-chloro-phenyl)-ethyl]-1H-tetrazole

This compound was prepared by the procedure described in Example 130,substituting5-benzo[1,3]dioxol-5-yl-3-bromomethyl-1-(2,5-dichloro-phenyl)-1H-pyrazole(prepared as in Method 1) for3-bromomethyl-5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazolein step A. HPLC: R_(t)=5.21 (Method A). MS (ESI): mass calculated forC₂₅H₁₇Cl₃N₆O₂, 538.05; m/z found, 539.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.46-7.41 (m, 2H), 7.32 (d, J=2.2 Hz, 1H), 7.26-7.23 (m, 2H), 7.14-7.04(m, 2H), 6.70 (d, J=7.9 Hz, 1H), 6.57 (dd, J=8.2, 1.9 Hz, 1H), 6.54 (d,J=1.6 Hz, 1H), 6.17 (br s, 1H), 5.96 (s, 2H), 5.02 (dd, J=8.5, 4.4 Hz,1H), 3.60 (dd, J=15.1, 8.8 Hz, 1H), 3.48 (dd, J=15.1, 4.4 Hz, 1H).

The compounds of Examples 133 and 134 were made according to thesynthetic methods outlined in Scheme J.

Example 133

(Ester-Arylation)

3-[5-(3,4-Dichloro-phenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazol-3-yl]-2-(3-dimethylamino-phenyl)-propionicacid

A. 6-(3,4-Dichloro-phenyl)-6-hydroxy-4-oxo-hex-5-enoic acid bis-lithiumsalt. To a 3-neck flask was added diethyl ether (120 mL) and lithiumbis(trimethylsilyl)amide (10.0 g, 59.9 mmol, 2.0 equiv) under nitrogen.The slurry was cooled to −78° C., then a solution of1-(3,4-dichloro-phenyl)-ethanone (11.3 g, 59.9 mmol, 2.0 equiv) indiethyl ether (120 mL) was added dropwise. The mixture was stirred at−78° C. for 30 min, then a solution of succinic anhydride (3.0 g, 29.9mmol, 1.0 equiv) in diethyl ether (60 mL) was added dropwise. Thereaction mixture was stirred at −78° C. for 1 h then allowed to warm toroom temperature and stirred 16 h. The resulting precipitate wasfiltered off, washed with diethyl ether (2×60 mL), and dried yielding ayellow powder (9.48 g, 99%), which was used in the next step withoutpurification or characterization.

B.3-[5-(3,4-Dichloro-phenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazol-3-yl]-propionicacid. To a round-bottom flask was added6-(3,4-dichloro-phenyl)-6-hydroxy-4-oxo-hex-5-enoic acid bis-lithiumsalt (9.48 g, 31.3 mmol, 1.0 equiv), 2,4-dichloro-phenyl hydrazinehydrochloride (6.66 g, 31.3 mmol, 1.0 equiv) and EtOH (250 mL) undernitrogen. The mixture was stirred at room temperature for 24 h. Thesolvent was removed, and the crude residue was partitioned between 5%HCl and diethyl ether (200 mL each). The layers were separated, and theaqueous layer was extracted with diethyl ether (2×100 mL). The combinedorganic layers were washed with water (100 mL) then brine (100 mL),dried (Na₂SO₄), and concentrated under reduced pressure. Purification byflash chromatography (25% ethyl acetate/dichloromethane) afforded thetitle intermediate (4.5 g, 33%). HPLC: R_(t)=3.04 (Method A). MS (ESI):mass calculated for C₁₈H₁₂Cl₄N₂O₂, 427.97; m/z found, 429/431 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆): 12.20 (br s, 1H), 7.82 (d, J=2.2 Hz, 1H), 7.68(d, J=8.5 Hz, 1H), 7.61-7.59 (m, 2H), 7.50 (d, J=2.2 Hz, 1H), 7.05 (dd,J=8.2, 1.9 Hz, 1H), 6.73 (s, 3H), 2.88 (t, J=7.4 Hz, 2H), 2.64 (t, J=7.4Hz, 2H).

C.3-[5-(3,4-Dichloro-phenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazol-3-yl]-propionicacid tert-butyl ester. To a 3-neck round bottom flask fitted with an aircondenser was added3-[5-(3,4-dichloro-phenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazol-3-yl]-propionicacid (1.0 g, 2.3 mmol, 1.0 equiv) and toluene (23 mL) under nitrogen.The mixture was heated to 80° C. then N,N-dimethyl-di-tert-butylacetal(2.36 g, 11.6 mmol, 5.0 equiv) was added dropwise (neat). The reactionmixture was heated at 80° C. for 1 h then additionalN,N-dimethyl-di-tert-butylacetal (2.36 g, 11.6 mmol, 5.0 equiv) wasadded. This mixture was stirred at 80° C. for 2 h then cooled to roomtemperature and partitioned between water (100 mL) and ether (100 mL).The organic layer was washed with 1 M sodium hydroxide (50 mL), water(50 mL) then brine (50 mL), dried (Na₂SO₄), and concentrated underreduced pressure. The crude material was then purified by flashchromatography (20% ethyl acetate/hexanes) to afford the desired ester(1.1 g, >99%). HPLC: R_(t)=3.59 (Method A). MS (ESI): mass calculatedfor C₂₂H₂₀Cl₄N₂O₂, 484.03; m/z found, 485.0 {M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): 7.81 (d, J=2.2 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.61-7.59 (m,2H), 7.48 (d, J=2.2 Hz, 1H), 7.05 (dd, J=8.2, 1.9 Hz, 1H), 6.71 (s, 1H),2.87 (t, J=7.4 Hz, 2H), 2.61 (t, J=7.4 Hz, 2H), 1.38 (s, 9H).

D.3-[5-(3,4-Dichloro-phenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazol-3-yl]-2-(3-dimethylamino-phenyl)-propionicacid tert-butyl ester. To a mixture of palladium(II) acetate (3 mg, 5mol %), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (10 mg, 5mol %) and lithium bis(trimethylsilyl)amide (0.55 mL, 0.55 mmol, 1.1equiv, 1.0 M solution in tetrahydrofuran) in toluene (0.5 mL) undernitrogen at −10° C., was added a solution of3-[5-(3,4-dichloro-phenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazol-3-yl]-propionicacid tert-butyl ester (243 mg, 0.50 mmol, 1.0 equiv) in toluene (1.0mL). This mixture was stirred at −10° C. for 10 min, then(3-bromo-phenyl)-dimethyl-amine (42 mg, 0.21 mmol, 0.45 equiv) intoluene (0.5 mL) was added. The resulting solution was allowed to warmto room temperature then was heated to 80° C. for 3 h. The reactionmixture was cooled to room temperature, and the reaction was quenchedwith satd aq ammonium chloride (1.0 mL). Water (10.0 mL) was added, andthe resulting mixture was extracted with diethyl ether (2×10 mL). Thecombined extracts were washed with brine (10 mL), dried (Na₂SO₄), andconcentrated under reduced pressure. The crude material was purified byreversed-phase HPLC to afford the desired aryl acetic acid ester (20 mg,16%). MS (ESI): mass calculated for C₃₀H₂₉Cl₄N₃O₂, 603.10; m/z found,604.1 [M+H]⁺.

E.3-[5-(3,4-Dichloro-phenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazol-3-yl]-2-(3-dimethylamino-phenyl)-propionicacid.3-[5-(3,4-Dichloro-phenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazol-3-yl]-2-(3-dimethylamino-phenyl)-propionicacid tert-butyl ester (20 mg, 0.03 mmol) was dissolved in 1:1trifluoroacetic acid/dichloromethane (1.0 mL) and stirred for 2 h. Thereaction mixture was concentrated under reduced pressure, and the cruderesidue was dissolved in 1:1 acetonitrile/water (2.0 mL). The solutionwas lyopholized to afford the title compound (18 mg, >99%). HPLC:R_(t)=2.60 (Method B). MS (ESI): mass calculated for C₂₆H₂₁Cl₄N₃O₂,547.04; m/z found, 548/550[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.81 (d,J=1.9 Hz, 1H), 7.60-7.58 (m, 3H), 7.45 (d, J=2.2 Hz, 1H), 7.18 (t, J=7.9Hz, 1H), 7.02 (dd, J=8.5, 2.2 Hz, 1H), 6.78 (m, 3H), 6.64 (s, 1H), 3.96(dd, J=8.8, 6.6 Hz, 1H), 3.36 (dd, J=15.1, 9.0 Hz, 1H), 2.93 (dd,J=15.1, 6.6 Hz, 1H), 2.91 (s, 6H).

Example 134

3-[5-(3,4-Dichloro-phenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazol-3-yl]-2-quinolin-8-yl-propionicacid

The title compound was prepared as described in Example 133,substituting 8-bromo-quinoline for (3-bromo-phenyl)-dimethyl-amine inStep D. HPLC: R_(t)=2.99 (Method B). MS (ESI): mass calculated forC₂₇H₁₇Cl₄N₃O₂, 555.01; m/z found, 556.1 [M+H]⁺.

The compounds of Examples 135-138 were made according to the syntheticmethods outlined in Scheme I.

Example 135

5-{3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole-3-yl]-2-m-tolyl-propylsulfanyl}-1H-[1,2,4]-triazole

A.3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propan-1-ol.To a 3-neck round-bottom flask charged with nitrogen was added3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid ethyl ester (see Method 2, product before hydrolysis; 798 mg, 1.57mmol, 1.0 equiv) and tetrahydrofuran (6.0 mL). The mixture was cooled to-78° C., then diisobutyl aluminum hydride (4.7 mL, 1.0 M solution intetrahydrofuran) was added dropwise. The reaction mixture was stirred at−78° C. for 30 min then allowed to warm to room temperature and stirred1 h. The mixture was then poured slowly into a satd aq solution ofRochelle salt (50 mL). Diethyl ether (50 mL) was added, and theresulting mixture was stirred for 3 h. The organic layer was dried(Na₂SO₄) and concentrated under reduced pressure to afford 732 mg of thedesired alcohol, which was used in the next step without purification.

B.3-(3-Bromo-2-m-tolyl-propyl)-5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole.To a 3-neck round-bottom flask was added phosphorus tribromide (599 mg,2.77 mmol, 1.5 equiv) and dichloromethane (10 mL). The mixture wascooled to 0° C., then a solution of3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propan-1-ol(690 mg, 1.48 mmol, 1.0 equiv) in dichloromethane (3.0 mL) was added.The reaction mixture was allowed to warm to room temperature then wasstirred for 16 h. The resulting mixture was loaded directly onto asilica gel column and purified by chromatography (25% ethylacetate/hexanes) giving the desired bromide (480 mg, 61%). HPLC:R_(t)=3.80 (Method B). MS (ESI): mass calculated for C₂₆H₂₃BrCl₂N₂O,528.04; m/z found, 529.0 [M+H]⁺.

C.5-{3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole-3-yl]-2-m-tolyl-propylsulfanyl]-1H-[1,2,4]-triazole.To a suspension of sodium hydride (4.0 mg, 60% dispersion in oil) inN,N-dimethylformamide (1.0 mL) at 0° C. was added a solution of2H-[1,2,4]triazole-3-thiol (10.0 mg, 0.1 mmol, 1.1 equiv) inN,N-dimethylformamide (1.0 mL). The mixture was stirred at 0° C. for 30min then a solution of3-(3-bromo-2-m-tolyl-propyl)-5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole(48 mg, 0.09 mmol, 1.0 equiv) in N,N-dimethylformamide (1.0 mL) wasadded. The reaction mixture was brought to room temperature then wasstirred for 2 h. The reaction was quenched with satd aq ammoniumchloride (1.0 mL), and the resulting mixture was diluted with water(10.0 mL), and extracted with ethyl acetate (3×10 mL). The combinedorganic layers were washed with water (10 mL) then brine (10 mL), dried(Na₂SO₄), and concentrated under reduced pressure. The crude residue waspurified by reversed-phase HPLC to yield the title compound (39 mg,80%). HPLC: R_(t)=3.26 (Method B). MS (ESI): mass calculated forC₂₈H₂₅Cl₂N₅OS, 549.12; m/z found, 550.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): 8.32 (br s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.35 (d, J=2.1 Hz,1H), 7.07-7.04 (m, 5H), 6.95 (dd, J=8.4, 21. HZ, 2H), 6.89 (d, J=9.0 Hz,2H), 6.31 (s, 1H), 3.70 (s, 3H), 3.48 (dd, J=12.9, 6.3 Hz, 1H), 3.36(dd, J=12.7, 8.2 Hz, 1H), 3.26 (m, 1H), 3.07 (dd, J=14.9, 6.4 Hz, 1H),2.91 (dd, J=14.9, 8.2 Hz, 1H), 2.21 (s, 3H).

Example 136

5-[3-(1,5-Di-p-tolyl-1H-pyrazol-3-yl)-2-m-tolyl-propane-1-sulfinyl]-1H-[1,2,4]triazole

To a cold (0° C., ice bath) solution of5-[3-(1,5-di-p-tolyl-1H-pyrazol-3-yl)-2-m-tolyl-propylsulfanyl]-1H-[1,2,4]triazole(177 mg, 0.37 mmol, 1.0 equiv) [prepared by substituting3-(1,5-di-p-tolyl-1H-pyrazol-3-yl)-2-m-tolyl-propionic acid ethyl ester(see Method 2, product before hydrolysis) for3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid ethyl ester in Step A of Example 135] in dichloromethane (2.0 mL)was added 3-chloroperoxy benzoic acid (90 mg, 0.41 mmol, 1.1 equiv). Thereaction mixture was stirred at 0° C. for 15 min, stirred at 40° C. for1 h, and then cooled to room temperature and stirred for 16 h. Thesolvent was evaporated under reduced pressure, and the crude materialwas purified by reversed-phase HPLC giving the desired sulfinyl triazole(165 mg, 90%). HPLC: R_(t)=2.88 (Method 8). MS (ESI): mass calculatedfor C₂₉H₂₉N₅OS, 495.21; m/z found, 496.2 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): 8.79 (s, 1H), 7.00-7.23 (m, 12 H), 6.30 (s, 0.5H), 6.14 (s,0.5H), 3.81 (dd, J=12.5, 3.7 Hz, 0.5H) 3.72(dd, J=12.9, 7.0 Hz, 0.5H),3.37-3.60 (m, 1.5H), 3.28-3.25 (m, 0.5H), 2.97-3.15 (m, 2.0H), 2.31-2.27(m, 9H).

Example 137

5-[3-(1,5-Di-p-tolyl-1H-pyrazol-3-yl)-2-m-tolyl-propane-1-sulfonyl]-1H-[1,2,4]triazole

To a flask was added5-[3-(1,5-di-p-tolyl-1H-pyrazol-3-yl)-2-m-tolyl-propane-1-sulfinyl]-1H-[1,2,4]triazole(Example 136; 25 mg, 0.05 mmol), hydrogen peroxide (0.15 mL, 30%solution in water) and acetic acid (0.1 ml). The mixture was heated at50° C. for 24 h and then cooled. Methanol (0.5 mL) andN,N-dimethylformamide (0.5 mL) were added to dissolve the resultingprecipitate. This solution was then purified directly by reversed-phasechromatography yielding the title compound (24 mg, 95%). HPLC:R_(t)=2.97 (Method B). MS (ESI): mass calculated for C₂₉H₂₉N₅O₂S,511.20; m/z found, 512.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 14.87 (br s,1H), 8.72 (s, 1H), 7.18 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 7.08(d, J=7.0 Hz, 1H), 7.07-7.04 (m, 3H), 7.01-6.99 (m, 3H), 6.95 (d, J=7.4Hz, 1H), 6.15 (s, 1H), 3.91 (d, J=6.6 Hz, 2H), 3.52-3.49 (m, 1H), 3.08(dd, J=14.7, 7.6 Hz, 1H) 2.91 (dd, J=14.5, 7.4 Hz, 1H), 2.31 (s, 3H),2.27 (s, 3H), 2.23 (s, 3H).

Example 138

5-{(S)-3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propane-1-sulfonyl}-1H-[1,2,4]triazole

The title compound was prepared as outlined in Example 137, substitutingthe S enantiomer of3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid ethyl ester [available by chiral separation of ester prepared inMethod 2] for the racemic3-[5-(3,4-dichlorophenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid ethyl ester in Step A. HPLC: R_(t)=2.94 (Method B). MS (ESI): masscalculated for C₂₈H₂₅Cl₂N₅O₃S, 581.11; m/z found, 582.3 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆): 14.87 (br s, 1H), 8.72 (s, 1H), 7.58 (d, J=8.5 Hz,1H), 7.43 (d, J=2.2 Hz, 1H), 7.14 (d, J=9.0 Hz, 2H), 7.08 (d, J=7.4 Hz,1H), 6.96-7.04 (m, 6H), 6.36 (s, 1H), 3.92 (d, J=6.3 Hz, 2H), 3.78 (s,3H), 3.53-3.50 (m, 1H), 3.09 (dd, J=14.5, 7.4 Hz, 1H), 2.92 (dd, J=14.5,7.7 Hz, 1H), 2.23 (s, 3H).

Example 139

3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl-1H-pyrazol-3-yl]-2-fluoro-2-m-tolyl-propionicacid

A.3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-fluoro-2-m-tolyl-propionicacid ethyl ester. To a round-bottom flask containing lithiumbis(trimethylsilyl)amide (0.47 mL, 1.0 M solution in tetrahydrofuran),and tetrahydrofuran (1.5 mL) at 0° C. under nitrogen, was added3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid ethyl ester (Method 2, product before hydrolysis; 200 mg, 0.39mmol, 1.0 equiv) in tetrahydrofuran (1.5 mL). The mixture was allowed tostir at 0° C. for 1 h, then a solution of sultam-F (109 mg, 0.51 mmol,1.5 equiv) in tetrahydrofuran (1.5 mL) was added, and the resultingsolution was stirred at 0° C. for 2 h. The reaction was quenched withsatd aq ammonium chloride (5 mL), and the resulting mixture was dilutedwith water (10 mL) and extracted with ethyl acetate (2×10 mL). Thecombined extracts were washed with water (10 mL) then brine (10 mL),dried (Na₂SO₄), and concentrated under reduced pressure. The cruderesidue was purified by reversed-phase HPLC giving the desiredalpha-fluoro ester (164 mg, 80%). HPLC: R_(t)=3.66 (Method B). MS (ESI):mass calculated for C₂₈H₂₅Cl₂FN₂O₃, 526.12; m/z found, 527.2 [M+H]⁺.

B.3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl-1H-pyrazol-3-yl]-2-fluoro-2-m-tolyl-propionicacid. The title compound was made as outlined in Method 2 (Scheme A) byhydrolysis of the ester described in Step A. HPLC: R_(t)=3.34. MS (ESI):mass calculated for C₂₆H₂₁Cl₂FN₂O₃, 498.09; m/z found, 499.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆): 7.59 (d, J=8.2 Hz, 1H), 7.45 (d, J=1.9 Hz, 1H),7.38-7.36 (m, 2H), 7.33 (t, J=7.4 Hz, 1H), 7.21 (d, J=7.1 Hz, 1H), 7.17(d, J=8.8 Hz, 2H), 7.07 (dd, J=8.2, 1.9 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H),6.48 (s, 1H), 3.77 (m, 1H), 3.78 (s, 3H), 3.42 (dd, J=17.0, 15.4 Hz,1H), 2.35 (s, 3H).

Example 140

4-(1,5-Di-p-tolyl-1H-pyrazol-3-yl)-3-m-tolyl-butyric acid

A. 4-(1,5-Di-p-tolyl-1H-pyrazol-3-yl)-3-m-tolyl-butyronitrile. To ascrew-cap vial were added3-(3-bromo-2-m-tolyl-propyl)-1,5-di-p-tolyl-1H-pyrazole (prepared by themethod of Example 67; 300 mg, 0.65 mmol, 1.0 equiv), sodium cyanide (160mg, 3.3 mmol, 5.0 equiv) and N,N-dimethylformamide (3.0 mL). The sealedmixture was then heated at 100° C. for 48 h. The reaction mixture wascooled to room temperature, diluted with water (10 mL), and extractedwith diethyl ether (3×10 mL). The combined extracts were washed withwater (4×10 mL) then brine (10 mL), dried (Na₂SO₄), and concentratedunder reduced pressure. The crude residue was purified by flashchromatography (25% ethyl acetate/hexanes) giving the desired nitrile(171 mg, 65%). MS (ESI): mass calculated for C₂₈H₂₇N₃, 405.22; m/zfound, 406.2 [M+H]⁺.

B. 4-(1,5-Di-p-tolyl-1H-pyrazol-3-yl)-3-m-tolylbutyric acid methylester. To a flask were added4-(1,5-di-p-tolyl-1H-pyrazol-3-yl)-3-m-tolyl-butyronitrile (100 mg, 0.24mmol), concd sulfuric acid (1.5 mL) and methanol (1.5 mL). The mixturewas heated to reflux for 24 h. The reaction mixture was cooled to roomtemperature, poured into ice (20 g) and neutralized with satd sodiumbicarbonate. The resulting solution was extracted with diethyl ether(3×10 mL), and the combined organic extracts were washed with water (10mL) then brine (10 mL), dried (Na₂SO₄), and concentrated under reducedpressure. The crude residue was purified by reversed-phase HPLC yieldingthe desired ester (86 mg, 82%). HPLC: R_(t)=3.43 (Method B). MS (ESI):mass calculated for C₂₉H₃₀N₂O₂, 438.23; m/z found, 439.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 7.19 (t, J=7.4 Hz, 1H), 7.01-7.13 (m, 11H), 6.15 (s,1H), 3.56 (s, 3H), 3.54-3.52 (m, 1H), 3.11-3.08 (m, 2H), 2.77-2.75 (m,2H), 2.36 (s, 3H), 2.32 (s, 6H).

C. 4-(1,5-Di-p-tolyl-1H-pyrazol-3-yl)-3-m-tolyl-butyric acid. The titlecompound was synthesized by Method 2 (Scheme A) by hydrolysis of theester described in Step B. HPLC: R_(t)=3.14 (Method B). MS (ESI): masscalculated for C₂₈H₂₈N₂O₂, 424.22; m/z found, 425.8 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆): 12.00 (br s, 1H), 6.98-7.19 (m, 12H), 6.23 (s,1H),3.39-3.37 (m, 1H), 3.00-2.87 (m, 2H), 2.71 (dd, J=15.5, 5.6 Hz, 1H),2.56 (dd, J=15.6, 9.4 Hz, 1H), 2.31 (s, 3H), 2.27 (s, 6H).

Example 141

5-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-4-m-tolyl-pentanoicacid

A.3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionaldehyde.To a flask containing3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propane-1-ol(prepared by the method of Example 67; 50 mg, 0.11 mmol, 1.0 equiv) anddichloromethane (2.0 mL) was added Dess-Martin reagent (89 mg, 0.21mmol, 2.0 equiv) in one portion. The reaction mixture was stirred atroom temperature for 30 min then poured into satd aq sodium bicarbonate(5.0 mL) containing sodium thiosulfate pentahydrate (5.0 equiv relativeto Dess-Martin reagent). The resulting mixture was then diluted withdichloromethane (3.0 mL) and stirred vigorously for 2 h. The resultingorganic layer was washed with water (5.0 mL) then brine (5.0 mL), dried(Na₂SO₄), and concentrated under reduced pressure, affording the desiredaldehyde, which was used in the next step without purification.R_(t)=3.57 (Method B). MS (ESI): mass calculated for C₂₆H₂₂Cl₂N₂O₂,464.11; m/z found, 465.0 [M+H]⁺.

B.5-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-4-m-tolyl-pent-2-enoicacid methyl ester. To a suspension of sodium hydride (30 mg, 60%dispersion in oil) in tetrahydrofuran (1.5 mL) at 0° C. was added methyldiethylphosphonoacetate (0.13 mL, 0.69 mmol, 1.0 equiv) neat. Themixture was stirred at 0° C. for 30 min, then a solution of3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionaldehyde(320 mg, 0.69 mmol, 1.0 equiv) in tetrahydrofuran (1.5 mL) was added.The reaction mixture was allowed to warm to room temperature and wasstirred 1 h. The reaction was quenched with 2 mL of water, and theresulting mixture was diluted with satd aq ammonium chloride (10 mL)then extracted with diethyl ether (3×20 mL). The combined extracts werewashed with water (20 mL) then brine (20 mL), dried (Na₂SO₄), andconcentrated under reduced pressure. The crude material was purified byflash chromatography (25% ethyl acetate/hexanes) giving the methyl ester(150 mg, 45%). HPLC: R_(t)=3.70 (Method B). MS (ESI): mass calculatedfor C₂₉H₂₆Cl₂N₂O₃, 520.13; m/z found, 521.2 [M+H]⁺.

C.5-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-4-m-tolyl-pentanoicacid methyl ester. To a flask containing ethyl acetate (1.0 mL), ethanol(1.0 mL) and a catalytic amount of Raney nickel was added5-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-4-m-tolyl-pent-2-enoicacid methyl ester (92 mg, 0.17 mmol). The reaction mixture was stirredunder H₂ (˜1 atm) for 2 h and then filtered through a CELITE® pad. Thefiltrate was concentrated under reduced pressure, and the crude residuewas purified by reversed-phase HPLC giving the desired ester (81 mg,91%). HPLC: R_(t)=3.68 (Method B). MS (ESI): mass calculated forC₂₉H₂₈Cl₂N₃O₃, 522.15; m/z found, 523.3 [M+H]⁺.

D.5-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-4-m-tolyl-pentanoicacid. The title compound was made by Method 2 (Scheme A) by hydrolysisof the ester of step C. HPLC: R_(t)=10.60 (Method A). MS (ESI): masscalculated for C₂₈H₂₆Cl₂N₂O₃, 508.13; m/z found, 509.0 [M+H]⁺. H¹ NMR(500 MHz, DMSO-d₆): 11.97 (br s, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.44 (d,J=2.2 Hz, 1H), 7.19 (t, J=7.7 Hz, 1H), 7.15 (d, J=9.0 Hz, 2H), 7.07-7.02(m, 4H), 6.96 (d, J=9.0 Hz, 2H), 6.42 (s,1H), 3.77 (s, 3H), 2.92-2.89(m, 3H), 2.29 (s, 3H), 2.00-1.99 (m, 3H), 1.80-1.77 (m, 1H).

General Experimental Details:

-   -   NMR spectra were obtained on a Bruker model DPX300 (300 MHz),        DPX400 (400 MHz), or DPX500 (500 MHz) spectrometer. Chemical        shifts are reported in ppm downfield of the tetramethylsilane        reference. The format of the ¹H NMR data below is: chemical        shift (multiplicity, coupling constant J in Hz, integration).    -   IR spectra were collected on a 2000 FTIR Perkin-Elmer        Spectrophotometer.    -   Mass spectra were obtained on an Agilent series 1100 MSD using        electrospray ionization (ESI) in either positive or negative        mode as indicated. The “mass calculated” for a molecular formula        is the monoisotopic mass of the compound.    -   Thin Layer Chromatography (TLC) was performed using silica gel        60 F₂₅₄ pre-coated plates (size, 2.5×7.5 cm; thickness, 250 μm).        The reaction products were detected by viewing the plates under        a UV lamp (254 nm).    -   Melting points were determined on either an Electrothermal        apparatus or on a Thomas-Hoover capillary melting point        apparatus and are uncorrected.    -   Elemental analysis was performed by QTI (Whitehall, N.J.).    -   Differential Scanning Calorimetry (DSC) was performed on a        Mettler-Toledo DSC instrument.

Reverse Phase HPLC (Method R):

Column: Zorbax Eclipse XDB-C8, 5 mm, 4.6×150 mm;

Flow rate: 0.75 mL/min; λ=220 & 254 nm;

Gradient (Acetonitrile/Water):

1) 8.0 min 1% -99% Acetonitrile

2) 10.0 min 99% Acetonitrile

Chiral HPLC (Method S):

Column: Chiralcel AD, 0.46×25 cm;

Mobile Phase: 85:15 Ethanol/Hexane;

Flow rate: 1 mL/min; λ=220 & 254 nm

Chiral HPLC (Method T):

Column: Chiralcel AD 0.46×25 cm;

Mobile Phase: 85:15 Ethanol/Hexane with 0.07% TFA;

Flow rate: 1 mL/min; λ=220 & 254 nm

Reverse Phase HPLC (Method U):

Column: Zorbax Eclipse XDB-C8, 5 μm, 4.6×150 mm;

Flow rate: 1.0 mL/min; λ=200 & 260 nm;

Gradient (Water/Acetonitrile):

1) 0.0 min 70% -30% Acetonitrile

2) 15.0 min 20% -80% Acetonitrile

3) 24.0 min 20% -80% Acetonitrile

4) 24.5 min 70% -30% Acetonitrile

5) 30.0 min 70% -30% Acetonitrile

Example 500

2-m-Tolyl-pent-4-ynoyl chloride

Step 1: 2-m-Tolyl-pent-4-ynoic acid. An oven dried, 1-L, 3-necked,round-bottomed flask was equipped with a magnetic stirring bar, N₂inlet, and a thermometer. The reaction vessel was charged with 39.2 mL(0.280 mol) of N,N-diisopropylamine and 250 mL of anhydrous THF. Thesolution was cooled to 0° C. and 112 mL of n-BuLi (2.5 M in hexanes,0.279 mol) was added. After stirring for 30 min, the reaction mixturewas cooled to −78° C. and a solution of m-tolylacetic acid (20.0 g,0.133 mole) in 100 mL of anhydrous THF was added. After 30 min,propargyl bromide (80% wt in toluene, 15.8 mL, 0.146 mole) was addeddropwise. After the addition, the reaction mixture was stirred at −78°C. for 2 h. The cooling bath was then removed and the reaction wasallowed to warm to rt. Satd. aq. NH₄Cl (150 mL) was added, followed by 1N HCl until pH=2, and the mixture transferred to a separatory funnelwith the aid of 200 mL of EtOAc. The layers were separated and theorganic layer was washed with H₂O (1×100 mL) and brine (1×100 mL), andwas dried over MgSO₄. After filtration the solvents were evaporatedunder reduced pressure to obtain a brown solid. The product was purifiedby recrystallization from hot hexane to obtain the desired acid as apale brown, crystalline solid (19.5 g, 78%). HPLC (Method R): R_(t)=8.26min. MS (ES+): mass calculated for C₁₂H₁₂O₂, 188.08; m/z found, 189.09[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.19-7.23 (m,1H), 7.08-7.11 (m, 3H),3.79 (t, J=9.9 Hz, 1H), 2.92 (ddd, J=16.6, 8.6, 2.5 Hz, 1H), 2.61 (ddd,J=16.6, 7.1, 2.5 Hz, 1 H), 2.34 (s, 3H), 1.96 (t, J=2.5 Hz, 1H).

Step 2: 2-m-Tolyl-pent-4-ynoyl chloride. An oven dried, 500-mL, 1-neckedround-bottomed flask was equipped with a magnetic stirring bar and N₂inlet. The reaction vessel was charged sequentially with 13 g (0.069mol) of 2-m-tolyl-pent-4-ynoic acid, 100 mL of CH₂Cl₂, and 0.1 mL ofDMF. Oxalyl chloride (7.3 mL, 0.082 mol) was added dropwise to thereaction. After the addition, the reaction mixture was stirred for 4 h.The solvent and excess reagents were removed by evaporation underreduced pressure to provide a brown oil. Bulb-to-bulb distillation underreduced pressure (167° C./5 Torr gave the desired acid chloride as apale orange oil (12.8 g, 90%). HPLC (Method R): R_(t) of methyl ester(quenching in MeOH)=9.35 min. ¹H NMR (400 MHz, CDCl₃): 7.15-7.18 (m,1H), 7.08-7.11 (m, 2H), 4.18 (t, 1H, J=7.5Hz), 2.97 (ddd, J=16.6, 8.6,2.5 Hz, 1H), 2.61 (ddd, J=16.6, 7.1, 2.5 Hz, 1H), 2.37 (s, 3H), 2.03 (t,J=2.5 Hz, 1H).

Example 501

(S)-2-m-Tolyl-pent-4-ynoic acid 1-ethoxycarbonyl-ethyl ester

An oven dried 1-L, 3-necked round-bottomed flask was equipped with amagnetic stirring bar, a rubber septa, and a N₂ inlet. The reactionvessel was charged with a solution of 2-m-tolyl-pent-4-ynoyl chloridefrom Example 500, Step 2 (12.8 g, 61.9 mmol) in 350 mL of toluene viacannula. To this mixture was then added 22.3 mL (0.206 mmol) ofN,N-dimethylethylamine. After stirring at rt for about 5 h, the reactionmixture was cooled to −78° C. and 8.6 mL (75 mmol) of ethyl(S)-(−)-lactate (neat) was added. After the mixture was stirred at thistemperature for 4 h, the cooling bath was removed and the reactionmixture was allowed to warm to rt overnight. Water (100 mL) was addedand the resulting mixture was transferred to a separatory funnel. Thelayers were separated and the organic layer was washed with H₂O (100 mL)and dried over MgSO₄. After filtration, the solvents were evaporatedunder reduced pressure. The crude product thus obtained was purified byfiltration through a pad of silica gel to obtain the lactate ester as ayellow oil (16.1 g, 90%). The product was found to be predominantly onediastereoisomer (82% de by ¹H NMR). HPLC (Method R): R_(t)=9.84 min. MS(ES+): mass calculated for C₁₇H₂₀O₄, 288.14; m/z found, 289.14 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.20-7.25 (m, 1H), 7.10-7.15 (m, 3H), 5.12 (dd,J=10.4, 7.0 Hz, 1H), 4.06 (dd, J=14.4, 7.0 Hz, 2H), 3.84 (t, J=8.0 Hz),2.95 (ddd, J=16.6, 8.6, 2.8 Hz, 1H), 2.66 (ddd, J=16.6, 7.1, 2.8 Hz,1H), 2.37 (s, 3H), 1.97 (t, J=2.5 Hz, 1H), 1.48 (d, J=7.0 Hz, 3H), 1.11(t, J=7.3 Hz, 3H).

Example 502

(S)-6-(3,4-Dichloro-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acid1-ethoxycarbonyl-ethyl ester

An oven dried, 1-L, 1-necked round-bottomed flask was equipped with amagnetic stirring bar and a N₂ inlet. The reaction vessel was chargedsequentially with 14.3 g (0.068 mol) of 3,4-dichlorobenzoyl chloride(solid), a solution of 16.5 g of (S)-2-m-tolyl-pent-4-ynoic acid1-ethoxycarbonyl-ethyl ester from Example 501 (57.2 mmol) in 75 mL ofanhydrous THF, and 75 mL of anhydrous toluene. N₂ was bubbled throughthe solution for about 5 min. The catalysts PdCl₂(PPh₃)₂ (0.10 g, 0.086mmol) and Cul (0.10 g, 0.52 mmol) were added, followed by 15 mL (13.8 g,0.138 mol) of N-methylmorpholine (NMM). The reaction mixture was stirredat rt for 28 h when TLC indicated almost complete consumption ofstarting materials. Water was added (200 mL) and the mixture transferredto a separatory funnel with the aid of 200 mL of EtOAc. The layers wereseparated and the organic layer was washed with H₂O (2×50 mL) and driedover MgSO₄. After filtration, the solvents were evaporated and the darkresidue obtained was purified by pad filtration on silica gel to yieldthe acetylenic ketone as a yellow oil (21 g, 80%). HPLC (Method R):R_(t)=11.09 min. MS (ES+): mass calculated for C₂₁H₁₈Cl₂O₃, 460.08; m/zfound, 461.09 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.03 (d, J=2.0 Hz, 1H),7.65 (dd, J=8.3, 2.0 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.25-7.29 (bm,1H), 7.13-7.16 (m, 3H), 5.13 (dd, J=10.4, 7.0 Hz, 1H), 4.10 (dd, J=14.4,7.2 Hz, 2H), 3.95 (t, J=8.0 Hz), 3.22 (dd, J=16.6, 7.6 Hz, 1H), 3.04(dd, J=16.6, 8.0 Hz, 1H), 2.37 (s, 3H), 1.48 (d, J=7.0 Hz, 3H), 1.15 (t,J=73 Hz, 3H).

Example 503

(S)-3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid 1-ethoxycarbonyl-ethyl ester

To a stirred solution of(S)-6-(3,4-dichloro-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acid1-ethoxycarbonyl-ethyl ester from Example 502 (15.5 g, 0.0336 mol) inTHF (150 mL) was added Cs₂CO₃ (8.8 g, 0.027 mol) followed by4-methoxyphenyl hydrazine HCl (6.5 g, 0.037 mol). The resulting slurrywas stirred at rt overnight and then slowly quenched with 1 N HCl untilpH 2-3. The mixture was transferred to a separatory funnel and extractedwith EtOAc (3×75 mL). The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to an oil. The crudeoil was purified by pad filtration on silica gel using EtOAc/hexanes toobtain the pyrazole as mixture of two regioisomers in 4:1 ratio (18.6 g,95%). Chiral HPLC (Method S): R_(t) (R,S)=5.6 min; (S,S)=6.3 min. ¹H NMR(400 MHz, CDCl₃): 7.31-7.07 (m, 8H), 6.91-6.86 (m, 3H), 6.23 (s, 1H),5.13 (dd, J=10.4, 7.0 Hz, 1H), 4.16 (m, 1H), 4.07 (dd, J=14.4, 7.2 Hz,2H), 3.82 (s, 3H), 3.51 (dd, J=14.9, 9.6 1H), 3.04 (dd, J=14.9, 6.3 Hz,1H), 2.37 (s, 3H), 1.42 (d, J=7.0 Hz, 3H), 1.12 (t, J=7.3 Hz, 3H).

Example 504

(S)-3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

A 500-mL, 1-necked round-bottomed flask equipped with a magneticstirring bar was charged with(S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid 1-ethoxycarbonyl-ethyl ester from Example 503 (18.5 g. 0.0318 mol),as a 4:1 mixture of regioisomers, in 150 mL of acetic acid. After theaddition of 2 N HCl (25 mL), the reaction mixture was heated at 85° C.using an oil bath. After 4 h, when TLC indicated complete hydrolysis ofthe lactate ester, the heating source was removed and reaction flaskcooled to rt. The mixture was concentrated under reduced pressure toremove most of acetic acid, and then 250 mL of EtOAc was added. TheEtOAc solution was then washed with H₂O (50 mL) and brine (50 mL), andthen dried over Na₂SO₄. The solvents were removed under reduced pressureto obtain the crude acid as a brown oil (15 g, 98%). HPLC (Method E)indicated the product to be a mixture of 2 regioisomers in a 4:1 ratio.Chiral HPLC (Method S): R_(t) (S isomer)=8.1 min (enantiomeric ratio of1:9 R/S). This mixture was subjected to the next step without anyadditional purification. MS (ES+): mass calculated for C₂₆H₂₂Cl₂N₂O₃,480.10; m/z found, 480.8 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.31-7.09 (m,8H), 6.91-6.86 (m, 3H), 6.21 (s, 1H), 4.12-4.08 (dd, J=5.8, 9.6 Hz, 1H),3.82 (s, 3H), 3.54-3.49 (dd, J=9.6, 14.9 Hz, 1H), 3.13-3.08 (dd, J=5.8,14.9 Hz, 1H), 2.35 (s, 3H).

Example 505

(S)-Sodium;3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate

A stirred solution of(S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid from Example 504 (15.3 g, 0.0318 mol), as a 4:1 mixture ofregioisomers, in THF (150 mL) was cooled to 0° C. After the addition of3.1 M NaOH, the resulting mixture was stirred for 2 h. The cooling bathwas removed and the mixture was concentrated under reduced pressure. Theresidue was dissolved in 100 mL of THF and CH₃CN (100 mL) was added. Thesolution was stirred at rt for about 30 min when precipitation started.The mixture was stirred for another 4 h and filtered. The solid sodiumsalt was collected and dried under vacuum to afford the sodium salt as awhite crystalline powder (10 g, 63%). Chiral HPLC (Method T): R_(t)=8.1min (>99.9% enantiomeric purity). MS (ES+): mass calculated forC₂₆H₂₂Cl₂N₂O₃, 481.38; m/z found, 482.2 [M+H]⁺. Mp 280-285° C. Opticalrotation [α]_(D)=+58.8 (c 0.1; EtOH). ¹H NMR (500 MHz, D₂O): 7.14-7.10(m, 2H), 6.99-6.96 (t, J=7.4 Hz, 1H), 6.82-6.80 (d, J=8.2 Hz, 2H),6.74-6.72 (d, J=7.4 Hz, 1H), 6.0-6.5 (m, 4H), 6.32-6.30 (d, J=8.0 Hz,1H), 5.60 (s, 1H), 3.82-3.80 (m, 1H), 3.42 (s, 3H), 3.37-3.28 (m, 2H),2.01 (s, 3H).

Example 506

2-m-Tolyl-pent-4-ynoic acid ethyl ester

A 2-L, 3-necked round-bottomed flask was equipped with a magneticstirring bar, a N₂ inlet, and a thermometer. The reaction vessel wascharged with 34.6 mL of N,N-diisopropylamine and 300 mL of anhydrousTHF. The solution was cooled to 0° C. and 100 mL of n-butyllithium (2.5M in hexanes) was added. After the addition, the solution was stirredfor 0.5 h and cooled to −78° C. To this solution, 40 mL of ethyl m-tolylacetate was added (neat). After stirring for 1 h, propargyl bromide (80%wt in toluene, 26.8 mL) was added dropwise (temperature ranged from −75to −78° C. during addition). The cooling bath was then removed and thesolution was allowed to warm to rt overnight. The reaction mixture wasquenched by adding satd. aq. NH₄Cl (100 mL) and the resulting mixturewas transferred to a separatory funnel with the aid of 100 mL of EtOAc.The layers were separated and the organic layer was washed with brineand dried over MgSO₄. After filtration, the solvents were evaporatedunder reduced pressure to yield a pale orange oil. Distillation underreduced pressure furnished the desired ester as colorless oil (40 g,82%). ¹H NMR spectrum of the product thus obtained indicated thepresence of about 5% of the starting material. The product was furtherpurified by fractional distillation using a Vigreux column (8 in.). Themain fractions distilling between 83 and 85° C. at 500 mTorr werecollected to yield the pure ester as a colorless liquid (35 g, 72%).TLC: R_(f)=0.54 (1:4 EtOAc/hexanes). HPLC (Method R): R_(t)=9.75 min. MS(ES+): mass calculated for C₁₄H₁₆O₂, 216.12; m/z found, 238.7 [M+Na]⁺.¹H NMR (400 MHz, CDCl₃): 7.19-7.23 (m, 1H), 7.08-7.11 (m, 3H), 4.09-4.22(m, 2H), 3.75 (dd, J=8.6, 7.1 Hz, 1H), 2.92 (ddd, J=16.6, 8.6, 2.5 Hz,1H), 2.61 (ddd, J=16.6, 7.1, 2.5 Hz, 1H), 2.34 (s, 3H), 1.95 (t, J=2.5Hz, 1H), 1.22 (t, J=7.1 Hz, 3H).

Example 507

6-(3,4-Dichloro-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acid ethyl ester

An oven dried 1-L, 1-necked round-bottomed flask was equipped with amagnetic stirring bar and a N₂ inlet. The reaction vessel was chargedsequentially with 17.4 g (83.2 mmol) of 3,4-dichlorobenzoyl chloride(solid), a solution of 15.0 g of 2-m-tolyl-pent-4-ynoic acid ethyl esterfrom Example 506 (69.4 mmol) in 100 mL of anhydrous THF, and 100 mL ofanhydrous toluene. Catalysts PdCl₂(PPh₃)₂ (0.10 g, 0.086 mmol) and Cul(0.10 g, 0.52 mmol) were then added, followed by 15.4 mL (14.2 g, 140mmol) of NMM. The reaction mixture was stirred at rt for 14 h when TLCindicated almost complete consumption of the starting material. Water(100 mL) and EtOAc (100 mL) were added to the reaction and the mixturewas transferred to a separatory funnel. The layers were separated andthe organic layer was washed with H₂O (2×100 mL), brine (50 mL), anddried over MgSO₄. After filtration, the solvents were evaporated toyield a yellow oil. The crude product was purified by silica gel columnchromatography (column: 14 cm OD, 12 cm in height; eluent: 1:9EtOAc/hexanes) to obtain the acetylenic ketone as a pale yellow oil (19g. 69%). TLC (1:4 EtOAc/hexanes): R_(f)=0.49. HPLC (Method R):R_(t)=11.09 min. MS (ES+): mass calculated for C₂₁H₁₈Cl₂O₃, 388.06; m/zfound, 389.18 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.03 (d, J=2.0 Hz, 1H),7.65 (dd, J=8.3, 2.0 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.25-7.29 (bm,1H), 7.13-7.16 (m, 3H), 4.12-4.25 (m, 1H), 3.88 (t, J=7.8 Hz, 1H),3.16(dd, J=17.2, 7.6 Hz, 1H), 2.98 (dd, J=17.2, 7.8 Hz, 1H), 2.35 (s,3H), 1.20 (t, J=7.4 Hz, 3H).

Example 508

3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid ethyl ester

To a stirred solution of6-(3,4-dichloro-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acid ethyl esterfrom Example 507 (9.55 g, 0.0245 mol) in THF (125 mL) was added Cs₂CO₃(8.8 g, 0.027 mol) followed by 4-methoxyphenyl hydrazine HCl (6.50 g,0.0372 mol). The resulting slurry was stirred at rt overnight and thenwas slowly quenched with 1 N HCl until pH 2-3. The mixture wastransferred to a separatory funnel and extracted with EtOAc (3×75 mL).The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to an oil. The crude oil was purified byfiltration chromatography (silica gel column: 14 cm OD, 10 cm in height,10 to 30% EtOAc/hexanes). The desired fractions were combined to afford9.46 g (76%) of the pyrazole ester as dark-orange oil. Chiral HPLC(Method S): R_(t) (R enantiomer)=5.6 min; R_(t) (S enantiomer)=6.3 min.MS (ES+): mass calculated for C₂₈H₂₆Cl₂N₂O₃, 509.44; m/z found, 510.9[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.31-7.07 (m, 8H), 6.91-6.86 (m, 3H),6.19 (s, 1H), 4.22-4.01 (m, 3H), 3.82 (s, 3H), 3.54-3.48 (dd, J=14.9,9.6 Hz, 1H), 3.11-3.06 (dd, J=14.9, 6.0 Hz, 1H), 2.35 (s, 3H), 1.20-1.16(t, J=7.3 Hz, 3H).

Example 509

(S)-3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

To a stirred solution of the Altus catalyst #8 (10.0 g) in phosphatebuffer (pH 7, 500 mL) was slowly added3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid ethyl ester from Example 508 (10.0 g, 0.0196 mol) in IPA/toluene(40 mL/15 mL) for over 30 min to form a slurried reaction mixture. Thereaction was monitored at 2 day intervals using chiral HPLC. After 24days, the reaction mixture was adjusted to pH 1-2 using 1 N HCl, andthen EtOAc (300 mL) was added. The mixture was stirred vigorously for 1h. The emulsion was filtered through a pad of CELITE®, washing withEtOAc (75 mL). The filtrate was transferred to a separatory funnel andthe layers were separated. The aqueous layer was extracted with EtOAc(2×75 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated to an oil. The crude oil was purified by filtrationchromatography (silica gel column: 14 cm OD, 10 cm in height, 1%MeOH/20% EtOAc/hexanes). After the unreacted pyrazole ester (4:1 R/S)was recovered (6.0 g, 60%), the eluent was changed to 2-3% MeOH/50%EtOAc/hexanes to obtain the desired pyrazole acid (3.8 g, 40%) as anoil. Chiral HPLC (Method S): R₁ (S enantiomer)=8.1 min. MS (ES+): masscalculated for C₂₆H₂₂Cl₂N₂O₃, 480.10; m/z found, 480.8 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.31-7.09 (m, 8H), 6.91-6.86 (m, 3H), 6.21 (s, 1H),4.12-4.08 (dd, J=9.6, 5.8 Hz, 1H), 3.82 (s, 3H), 3.54-3.49 (dd, J=14.9,9.6 Hz, 1H), 3.13-3.08 (dd, J=14.9, 5.8 Hz, 1H), 2.35 (s, 3H).

Example 509a

Enzymatic resolutions were also performed with lipases such as Mucormiehei, lyo; Rhizomucor miehei; and Candida cyclindracea, according tothe procedures described in Example 509. The yield in the enzymaticresolutions with lipase Mucor miehei, lyo, was substantially the same asthat described in Example 509.

Example 510

(S)-Sodium;3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate

To a stirred solution of(S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid from Example 509 (3.8 g, 7.9 mmol) in THF (40 mL) was added 4.4 MNaOH at rt. The mixture was stirred for 60 min, and then wasconcentrated to an oil under reduced pressure using a rotary evaporatorwith a bath temperature of 25-30° C. The residue was diluted in THF (25mL) and CH₃CN was added whereupon precipitation occurred. The solidswere stirred for 2 h, then were filtered and washed with CH₃CN to affordthe desired sodium salt (3.34 g, 68%) as a white solid. Chiral HPLC(Method T): R_(t)=7.1 min (>99.9% enantiomeric purity). MS (ES+): masscalculated for C₂₆H₂₂Cl₂N₂O₃, 480.10; m/z found, 481.0 [M+H]⁺. Mp280-285° C. Optical rotation [α]_(D)=+58.8 (c0.1; EtOH). ¹H NMR (500MHz, D₂O): 7.14-7.10 (m, 2H), 6.99-6.96 (t, J=7.4 Hz, 1H), 6.82-6.80 (d,J=8.2 Hz, 2H), 6.74-6.72 (d, J=7.4 Hz, 1H), 6.0-6.5 (m, 4H), 6.31 (d,J=8.0 Hz, 1H), 5.60 (s, 1H), 3.82-3.80 (m, 1H), 3.42 (s, 3H), 3.37-3.28(m, 2H), 2.01 (s, 3H).

Example 511

3,4-Dichloro-N-methoxy-N-methyl-benzamide

N,O-Dimethylhydroxylamine hydrochloride (1.48 kg, 14.9 mol) wassuspended in EtOAc (16 L) and warmed to 35° C. A solution of3,4-dichlorobenzoyl chloride (3.00 kg, 13.9 mol) in EtOAc (8 L) wasadded, followed by addition of DIPEA (5.45 ml, 31.2 mol) whilemaintaining the temperature below 40° C. The reaction suspension wasstirred for 1 h. When TLC analysis confirmed reaction completion by thedisappearance of starting material, the reaction mixture was cooled tort and H₂O (10 L) was added to achieve a clear, biphasic solution. Afterremoving the aqueous layer, the organic layer was dried (Na₂SO₄) andconcentrated to afford the title compound (3.49 kg, 100%) as an oil.Upon sitting at rt, the product crystallized. IR (KBr pellet): 3445,3258, 3091.6, 2981.4, 2945.5, 1942.4, 1645.6, 1588.6, 1557.4, 1462.9,1414.5, 1368, 1386.2,1262, 1209, 1130, 1112.5, 1071.8, 1030.9, 100.9,893.8. MS (ES+): mass calculated for C₉H₉Cl₂NO₂, 233.00; m/z found 234.0[M+H]⁺. Mp: 39.5-43.2° C. ¹H NMR (400 MHz, CDCl₃): 7.80 (d, J=2 Hz, 1H),7.54 (dd, J=8.4, 2.0 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 3.54 (s, 3H), 3.34(s, 3H). ¹³C NMR (100 MHz, CDCl₃): 167.2, 135.0, 133.9, 132.4, 130.7,130.2, 127.9, 61.5, 33.7.

Example 512

1-(3,4-Dichlorophenyl)-4-[(tetrahydro-2H-pyran-2-yl)oxy]-2-butyn-1-one(2a)

To a mixture of 3,4-dichloro-N-methoxy-N-methyl-benzamide from Example511 (0.68 g, 2.9 mmol) and tetrahydro-2-(2-propynyloxy)-2H-pyran (0.40mL, 2.9 mmol) in 3.5 mL of dry THF at −25° C. was added lithiumbis(trimethylsilyl)amide (LHMDS, 1 M in THF) between −25° C. and −18° C.The reaction mass was stirred at that temperature range for 1 h. Thereaction was quenched with 10 mL of 1 M citric acid and was allowed towarm to 10° C. EtOAc (5 mL) was added and the mass was stirred for 15min. The pH of the aqueous layer was 5. The layers were separated andthe organic layer was concentrated to give a light yellow oil (110%,including residual solvent). HPLC (Method U): R_(t)=15.42 min. MS (ES+):mass calculated for C₁₅H₁₄Cl₂O₃, 312.03; m/z found, 325.1 [M+Na]⁺. ¹HNMR (400 MHz, CDCl₃): 8.19 (d, J=2 Hz, 1H), 7.95 (dd, J=8.4, 2.1 Hz,1H), 7.57 (d, J=8.4 Hz, 1H), 4.94-4.81 (m, 1H), 4.56 (s, 2H), 3.97-3.82(m, 1H), 3.71-3.55 (m, 1H), 1.91-1.54 (m, 6H). ¹³C NMR (100 MHz, CDCl₃):175.0, 139.0, 136.0, 133.4, 131.4, 131.2, 130.8, 128.3, 97.7, 92, 82.9,62.2, 54.2, 30.1, 25.2, 18.9.

Example 513

(E)-1-(3,4-Dichlorophenyl)-3-(methoxymethylamino)-4-[(tetrahydro-2H-pyran-2-yl)oxy]-2-buten-1-one

MS (ES+): mass calculated for C₁₇H₂₁Cl₂NO₄, 373.08; m/z found, 374.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.95 (d, J=2.1 Hz, 1H), 7.69 (dd,J=8.4, 2.1 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 6.12 (s, 1H), 5.13 (d, J=12Hz, 1H), 4.79-4.77 (m, 1H), 4.76 (d, J=11.5 Hz, 1H), 3.70 (s, 3H),3.88-3.86 (m, 1H), 3.30 (s, 3H), 1.83-1.50 (m, 3H), 1.49-1.21 (m, 4H).

Example 514

(Z)-1-(3,4-Dichlorophenyl)-3-hydroxy-4-[(tetrahydro-2H-pyran-2-yl)oxy]-2-buten-1-one

3,4-Dichloro-N-methoxy-N-methyl-benzamide (Example 511, 4.90 kg, 20.9mol) and tetrahydro-2-(2-propynyloxy)-2H-pyran (3.06 kg, 21.4 mol),which was prepared by methods known to those skilled in the art, weredissolved in THF (28.6 L) at rt. After cooling to between −10 and −15°C., LHMDS (1 M in THF, 19.76 kg, 22.19 mol) was added. When HPLCanalysis indicated the disappearance of the starting material, thereaction mixture was warmed to 0° C. and 1 M aq. citric acid (34.0 L)was added. Next, EtOAc (20.0 L) was added and the resulting mixture wasstirred for 15 min. After removing the aqueous layer, the organic layerwas washed with brine (30.0 L) and the desired product was obtained as asolution, which was used in the next step without isolation. HPLC(Method U): R_(t)=16.24 min. MS (ES+): mass calculated for C₁₅H₁₆Cl₂O₄,330.04; m/z found, 331.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 15.7 (bs, 1H),7.99 (d, J=2 Hz, 1H), 7.71 (dd, J=8.4, 2.1 Hz, 1H), 7.53 (d, J=8.4Hz,1H), 6.45 (s, 1H), 4.72-4.70 (m, 1H), 4.39 (d, J=16.8 Hz, 1H), 4.33(d, J=16.8 Hz, 1H), 4.28-4.25 (m, 1H), 3.91-3.83 (m,1H), 2.04-1.43 (m,6H). ¹³C NMR (100 MHz, CDCl₃): 193.5, 179.2, 135.4, 133.2, 131.9, 129.4,127.7, 124.8, 97.5, 92.4, 67.1, 61.1, 29.0, 23.9, 17.9.

Example 515

5-(3,4-Dichlorophenyl)-1-(4-methoxyphenyl)-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-1H-pyrazole

4-Methoxyphenylhydrazine hydrochloride (3.88 kg, 21.8 mol) and K₂CO₃(3.21 kg, 23.2 mol) were added to a THF/EtOAc solution containing(Z)-1-(3,4-dichlorophenyl)-3-hydroxy-4-[(tetrahydro-2H-pyran-2-yl)oxy]-2-buten-1-one(Example 514) at 0-10° C. The resultant suspension was stirred andallowed to warm to rt overnight (16 h). When HPLC analysis indicated thedisappearance of the starting material, the reaction mixture wasfiltered. The organic reaction filtrate was washed with 1 M aq. citricacid (34.0 L), followed by 10% aq. NaCl (50.0 L) and the resultingproduct solution was used in the next synthetic step without isolation.HPLC (Method U): R_(t)=16.22 min. MS (ES+): mass calculated forC₂₂H₂₂Cl₂N₂O₃, 432.10; m/z found, 455.1 [M+Na]⁺. ¹H NMR (400 MHz,CDCl₃): 7.39 (d, J=1.9 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.19 (dd, J=6.8,2.2 Hz, 2H), 6.96 (dd, J=8.1, 2.1 Hz, 1H), 6.87 (dd, J=2.1, 7 Hz, 2H),6.58 (s, 1H), 4.86 (d, J=12 Hz, 1H), 4.83-4.81(m, 1H), 4.60 (d, J=12 Hz,1H), 3.99-3.84 (m, 1H), 3.82 (s, 3H), 3.78-3.74 (m, 1H), 1.91-1.52 (m,6H). ¹³C NMR (100 MHz, CDCl₃): 159.5, 150.7, 141.8, 133.0, 132.7, 130.9,130.8, 130.6, 128.1, 127.1, 114.7, 107.7, 98.6, 63.2, 62.6, 60.8, 55.9,30.9, 25.8, 21.4, 19.7, 14.6.

Example 516

[5-(3,4-Dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-methanol

A solution of p-toluenesulfonic acid (1.22 kg, 6.28 mol) in methanol(20.0 L) was added to the THF/EtOAc solution of5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-1H-pyrazole(Example 515) at rt and the resulting mixture was stirred overnight (18h). When HPLC analysis indicated the disappearance of the startingmaterial, the reaction mixture was concentrated to remove methanol. Theresulting mixture was washed with 10% aq. NaHCO₃ (40.0 L) followed bybrine (40.0 L). The organic layer was added to n-heptane and theresultant suspension was filtered, washed, and vacuum dried to afford[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-methanol(4.65 kg, 63.7% over 3 chemical steps) as a solid. Data comparedfavorably with that obtained for Example 1, Step C.

Example 517

Methanesulfonic acid5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-ylmethyl ester

Triethylamine (3.25 L, 23.3 mol) was added to a solution containing[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-methanol(Example 516, 5.18 kg, 14.8 mol) in THF (25.2 L) and toluene (6.3 L) atrt under N₂. The reaction mixture was heated to 35° C. andmethanesulfonyl chloride (1.82 L, 23.5 mol) was added slowly maintainingthe temperature between 35-45° C. The reaction mixture was stirred foran additional 2 h at 45° C. When HPLC analysis indicated thedisappearance of the starting material, the reaction mixture was cooledto rt and quenched with 10% aq. NaCl (6.3 L). The organic layer waswashed with brine (5.0 L) and the desired mesylate was used in solutionin the next synthetic step without isolation. Data compared favorablywith that obtained for Example 1, Step D.

Example 518

5-(3,4-Dichlorophenyl)-3-iodomethyl-1-(4-methoxyphenyl)-1H-pyrazole

Sodium iodide (4.06 kg, 27.1 mol) was added to the THF/toluene solutionof methanesulfonic acid5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-ylmethyl ester(Example 517, 6.32 kg, 14.8 mol). The resulting reaction mixture washeated at 40° C. for 6 h and then allowed to cool to rt overnight. WhenHPLC analysis indicated the disappearance of the starting material, thereaction was quenched with 28% aq. sodium thiosulfate (6.3 L). Theorganic layer was washed with sat. aq. NaHCO₃ (6.3 L), brine (6.3 L),then dried (MgSO₄). After filtration to remove the drying agent, thedesired product was obtained in a solution, which was used in the nextsynthetic step without isolation. Chemical characterization dataobtained herein for the title compound is not duplicated in this Examplein light of the same data given in Example 1, Step E.

Example 519

(3aS,8aR)-3-(2-m-Tolyl-acetyl)-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one

(3aS-cis)-(−)-3,3a,8,8a-Tetrahydro-2H-indeno[1,2-d]-oxazol-2-one (4.00kg, 22.8 mol) and m-tolylacetic acid (6.86 kg, 45.7 mol) were stirred intoluene (40.0 L) at rt. Triethylamine (9.25 kg, 91.3 mol) was added,followed by a solution of pivaloyl chloride (5.6 L) in toluene (8 L) andheated at 90° C. for 10 h. When HPLC analysis indicated thedisappearance of the starting material, the reaction was cooled to rtand H₂O (20.0 L) was added. After removing the aqueous layer, theorganic layer was washed with sat. aq. NaHCO₃ (20.0 L) followed by brine(20.0 L). The organic layer was vacuum-distilled to a volume of 14 L andn-heptane (70.0 L) was added to precipitate the product. The resultantsuspension was filtered, washed, and vacuum dried to afford the desiredoxazolone (6.22 kg, 88.6%) as an off-white fluffy solid. Chemicalcharacterization data obtained herein for the title compound is notduplicated in this Example in light of the same data given in Example 1,Step F.

Example 520

(2S,3aS,8aR)-3-{3-[5-(3,4-Dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionyl}-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one

To a stirred solution containing(3aS,8aR)-3-(2-m-tolyl-acetyl)-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one(Example 519, 5.54 kg, 18.0 mol) in THF (22.2 L) was added sodiumbis(trimethylsilyl)amide (NaHMDS, 1 M in THF, 19.8 L, 19.8 mol) at <−35°C. The mixture was stirred for 45 min between −35 and −70° C., thentreated with the THF/toluene solution containing5-(3,4-dichlorophenyl)-3-iodomethyl-1-(4-methoxyphenyl)-1H-pyrazole(Example 6, 6.79 g, 14.8 mol). The reaction mixture was stirred at <−35°C. for 2 h, and then was allowed to warm to rt overnight. When HPLCanalysis indicated the disappearance of the starting material, thereaction was quenched with H₂O (13.6 L). Toluene (10.5 L) was then addedand after removing the aqueous layer, the resulting solution of theproduct oxazolone was used in the next synthetic step without isolation.Chemical characterization data obtained herein for the title compound isnot duplicated in this Example in light of the same data given inExample 1, Step G.

Example 521

(S)-3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid

To a stirred THF/toluene solution containing3-{3-[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionyl}-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one(Example 520, 9.45 kg, 14.8 mol) at 0-10° C. was added H₂O (5.25 L) and30% hydrogen peroxide (4.35 L, 42.6 mol) followed by 19% aq. LiOH (9.40,42.6 mol). The reaction mixture was stirred between 0-10° C. for 2 h.When HPLC analysis indicated the disappearance of the starting material,the reaction was quenched between 0-10° C. with 1.5 N sodiummeta-bisulfite solution (8.0 L) maintaining the pH at 9-10. The quenchedreaction mixture was then acidified to pH 1-2 using 6 N HCl (8.4 L).After removing the aqueous layer, ˜60.0 L of the organic phase wasremoved under reduced pressure, and EtOAc (8.5 L) was added. Theresultant suspension was filtered and washed. The filtrate, containingthe desired acid, was used directly in the next synthetic step withoutisolation. Chemical characterization data obtained herein for the titlecompound is not duplicated in this Example in light of the same datagiven in Example 1, Step H.

Example 522

(S)-Sodium;3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate

To a stirred solution containing(S)-3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid (Example 521, 12.67 kg, 26.34 mol) at rt was added THF (26.5 L) and4 N NaOH (6.60 L). After stirring for 2 h, the reaction mixture wasconcentrated to ˜55% of the solvent volume and CH₃CN (100.0 L) was addedto precipitate the product. The resultant suspension was filtered,washed, and vacuum-dried to afford the desired propionate sodium salt(9.05 kg, 61.0% over 5 chemical steps) as an off-white solid.Christalline; melting point 301.0° C. by DSC. Chemical characterizationdata obtained herein for the title compound is not duplicated in thisExample in light of the same data given in Example 505.

Example 523

Meglumine salt (Table A). The meglumine salt was prepared according tothe following procedure:(S)-3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionicacid was prepared by dilution of (S)-sodium;3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate(Example 522) with EtOAc and neutralization of the sodium salt with 3 Naq. HCl. The resulting solution was treated with the appropriate base (1molar equiv) and stirred. The solution was then partially concentratedand was usually treated with an anti-solvent to obtain a crystallinesolid. This crude solid was usually further purified by re-slurryingwith an appropriate solvent, filtering, and drying the solids. Uponconcentration, an oily solid precipitated. It was triturated withhexanes, collected, and dried overnight at 50° C. under vacuum.

Example 524

Tromethamine salt. The tromethamine salt was prepared according to theprocedure described in Example 523. After stirring, the solvent wasremoved in vacuo. The resultant solids were dissolved in methanol, andconcentrated again. The resulting solids were finally re-slurried with1:1 EtOAc/hexanes at rt. The slurry was filtered and solids were driedunder nitrogen. Semicrystalline.

Example 525

Tributylamine salt. The free acid was prepared according to theprocedure described in Example 523, and then was concentrated to an oil.This material was solubilized in IPA (50 mL) and t-butylamine was added.The resultant slurry was stirred for 2 h at rt and filtered. The solidswere dried at 40° C. overnight under vacuum. Crystalline; melting point173.29° C. (decomposes), by DSC.

Example 526

Potassium salt. The potassium salt was prepared according to theprocedure described in Example 523. After stirring, the solvent wasremoved in vacuo. The resultant residue was dissolved in toluene, andconcentrated again. The resulting residue was triturated with n-heptaneto yield an oily solid which was dried at 40° C. under vacuum.Semicrystalline.

Example 527

Ethylene diamine salt. The free acid was prepared according to theprocedure described in Example 523, and then was concentrated to an oil.The acid was solubilized in EtOAc and ethylene diamine was added. CH₃CNwas added and the resultant slurry was stirred for 2 h. The solids werethen filtered and air-dried. Crystalline; melting point 150.45° C., byDSC.

Assay Method

Cell Culture

CHO—K1 cells that had undergone stable transfection with the CCK-1receptor were grown in DMEM supplemented with L-glutamine (2 mM),penicillin (50 units/mL) and streptomycin (50 μg/mL). Cells werecultured under continuous G418 selection (2 mM) and were harvested usinga rubber cell scraper. CHO—K1 cells were sub-cultured a maximum of tentimes before being reseeded from the original stocks.

Membrane Preparation

Membranes were prepared from the stably transfected CHO—K1 cells. Frozencell pellets (−40° C.) were thawed in 14 mL of buffer A (10 mM HEPES,130 mM NaCl, 4.7 mM KCl, 5 mM MgCl, 1 mM EGTA and 15.4 mg/100 mLbacitracin at pH 7.2), adapted from Harper et al. (Br. J. Pharmacol.(1996) 118, pp 1717-1726). The thawed pellets were homogenized using aPolytron PT-10 (7×1 s). The homogenates were centrifuged for 5 min at1500 rpm (600× g), and the resulting pellets were discarded. Thesupernatants were re-centrifuged in order to collect thereceptor-membrane pellets (25 min 15,000 rpm; 39,800× g), which werere-suspended in buffer A.

Incubation Conditions

All assays were conducted in 96-well plates (GF/B millipore filterplates) using buffer A, with 0.3 μM PD-134,308, for the dilutions. TheCCK-2 receptor ligand was included to eliminate the contribution of thisreceptor subtype to the binding. For the optimal cell numberdetermination experiments 20 pM [125I]-BH—CCK-8S (50 μL 60 pM solution)was incubated with a range of cell concentrations (2.5×105 to 12.5×105cells/well) in a total volume of 150 μL. Total binding of[125I]-BH—CCK-8S was determined in the presence of 15 μL of buffer A.Non-specific binding of [125I]-BH—CCK-8S was determined in the presenceof 15 μL of 100 μM 2-naphthalenesulphonyl L-aspartyl-(2-phenethyl)amide(2-NAP: see R. A. Hull et al., Br. J. Pharmacol. (1993) 108,pp 734-740),a CCK-1 receptor selective antagonist that is structurally unrelated tothe radioligand [125I]-BH—CCK-8S. The assay preparation was incubatedfor 1 h at 21±3° C., and then the assay was terminated upon rapidfiltration of the preparation under reduced pressure. The loaded filterswere washed three times using undiluted PBS (100 μL), and then theresidues were transferred to 5 mL scintillation tubes. Boundradioactivity was determined using a gamma counter (count time=1 min).From these experiments a cell concentration of 1 pellet in 40 mL ofbuffer (2.5×106 cells/mL) was chosen for use in other assays (below). Tovalidate the radioligand concentration and incubation time for theassay, saturation and kinetic binding studies were also conducted (seeM. F. Morton, The Pharmacological Characterization of CholecystokininReceptors in the Human Gastrointestinal Tract. PhD Thesis, University ofLondon, 2000). The affinity of novel compounds was estimated byincubating membrane preparations with 15 μL of competing ligand (0.1pM-1 mM) for 60 min at 21±3° C. The assay was then terminated accordingto the procedure outlined above.

Data Analysis

The pKi values were determined using the equation of Cheng and Prusoff(Biochem. Pharmacol. (1973) 22, pp 3099-3108):$K_{i} = \frac{{IC}_{50}}{1 + \frac{\lbrack L\rbrack}{K_{D}}}$

To circumvent problems associated with computer-assisted data analysisof compounds with low affinity, the data obtained in the current studywere weighted according to a method described by Morton (2000). Inbrief, 100% and 0% specific binding were defined independently usingtotal binding and binding obtained in the presence of a highconcentration of the reference antagonist, 2-NAP. TABLE Example pKiExample pKi Example pKi 1 8.0 198 8.1 56 7.3 2 8.0 208 5.5 80 7.9 3 6.6210 7.9 92 8.2 4 8.0 211 7.9 93 6.6 7 8.1 221 7.8 105 6.5 18 7.4 246 7.447 6.7 19 7.5 77 7.8 51 8.3 21 6.8 106 7.2 303 5.9 24 7.7 322 7.4 3055.7 26 7.1 328 7.7 308 7.2 27 8.2 334 7.0 311 7.7 28 5.9 71 7.6 48 7.129 7.4 72 7.3 50 7.0 31 6.0 261 7.9 79 6.9 32 7.2 262 7.9 82 5.9 37 7.764 7.3 83 7.2 40 8.1 65 5.7 88 7.4 42 8.2 66 7.7 90 6.1 43 7.0 68 6.6 868.4 46 7.7 74 8.2 87 7.6 145 7.8 129 7.8 91 7.9 148 7.8 131 6.9 101 7.8151 6.7 132 8.0 104 7.4 152 7.9 136 8.2 349 7.1 153 7.8 137 8.0 352 7.5155 8.0 138 7.5 75 7.1 157 7.9 335 7.5 110 7.9 167 7.9 54 7.4 111 8.4168 8.1 58 6.3 112 8.4 170 8.1 59 8.5 115 8.2 177 7.9 60 8.3 118 8.3 1817.8 271 7.8 120 8.0 182 7.9 275 7.7 121 8.1 189 7.4 276 8.2 122 8.8 1908.0 287 7.7 123 6.6 195 8.0 52 8.0 124 7.4 363 6.1

Having described the invention in specific detail and exemplified themanner in which may be carried into practice, it will be apparent tothose skilled in the art that innumerable variations, applications,modifications, and extensions of the basic principles involved may bemade without departing from its spirit or scope. It is to be understoodthat the foregoing is merely exemplary and the present invention is notto be limited to the specific form or arrangements of parts hereindescribed and shown.

1. A compound selected from the group consisting of3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionateand its sodium salt. 2.(Z)-3-[5-Benzo[1,3]dioxol-5-yl-1-(2,5-dichloro-phenyl)-1H-pyrazol-3-yl]-2-(3-chloro-phenyl)-acrylicacid. 3.5-{(S)-2-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-1-m-tolyl-ethyl)-1H-tetrazole.